Jonathan U. Peled, Alan M. Hanash, and Robert R. Jenq

Hematology 2016 2016:119-127

Role of the intestinal mucosa in acute gastrointestinal GVHD


Intestinal graft-versus-host disease (GVHD) remains a significant obstacle to the success of allogeneic hematopoietic cell transplantation. The intestinal mucosa comprises the inner lining of the intestinal tract and maintains close proximity with commensal microbes that reside within the intestinal lumen. Recent advances have significantly improved our understanding of the interactions between the intestinal mucosa and the enteric microbiota. Changes in host mucosal tissue and commensals posttransplant have been actively investigated, and provocative insights into mucosal immunity and the enteric microbiota are now being translated into clinical trials of novel approaches for preventing and treating acute GVHD. In this review, we summarize recent findings related to aspects of the intestinal mucosa during acute GVHD.

Learning Objectives

  • Recall the elements and functions of the intestinal mucosa and intestinal microbiota
  • Describe changes that occur in the intestinal microbiota with GVHD
  • Describe changes that occur in the intestinal mucosa with GVHD


Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative treatment of many benign and malignant hematological diseases but is also associated with significant toxicities. One of the major limitations to allogeneic HCT is graft-versus-host disease (GVHD). The acute form of GVHD, occurring in approximately 50% of patients, depending on the series studied, leads to potentially life-threatening dysfunction of the gut, liver, skin, and hematopoietic organs. The chronic form, which occurs in up to 40% of patients, can be severely debilitating because of a diverse array of pathologies including sclerosis, fibrosis, and exocrine gland dysfunction. Development of either acute or chronic GVHD is the second leading cause of death (after malignant relapse) in allogeneic HCT recipients.

In the 1970s, researchers evaluated allogeneic HCT in mice that were maintained from birth in isolators devoid of microbes1 or that were receiving gut-decontaminating antibiotics,2 and found that both interventions resulted in acute GVHD that was very mild. This indicated an important contributory role of the microbial flora to the development of acute GVHD. The intestinal tract harbors the greatest density of commensal microbes and is also one of the most important target organs of acute GVHD. Interactions between the allogeneic HCT recipient’s intestinal epithelium, stroma, and immune cells with the luminal commensals may thus play a major role in the pathophysiology of acute GVHD. However, the specific nature of these interactions and the best approaches to target this pathophysiology for prevention or treatment of GVHD have not been fully elucidated. In recent years, an increased focus on examining aspects of intestinal mucosal biology3 and advances in approaches to characterize complex mixtures of microorganisms using nucleotide sequencing4 have resulted in a better understanding of how this interplay participates in the development and maintenance of GVHD. In this review, we summarize recent efforts that have examined the role of the intestinal mucosa in the setting of acute GVHD.

Structure of the intestine

The intestinal mucosa is the innermost of 4 concentric histological layers found throughout most of the intestinal tract and is followed by the submucosa, the muscularis externa, and the serosa.5 The mucosa itself is further subdivided into 3 layers. The epithelium is a single-cell layer lining the interior lumen of the gastrointestinal tract. Immediately adjacent to the epithelial layer is the lamina propria, an interstitial tissue with a rich vascular and lymphatic network and abundant leukocytes. The third is the muscularis mucosae, which is composed of smooth muscle fibers.

Within the epithelium there are many individual cell types, each with its own specialized functions, including nutrient absorption and barrier function, production of mucus, production of antimicrobial molecules, production of growth factors, and cellular regeneration.5 Table 1 summarizes the functions of several important intestinal epithelial cell populations. Intestinal epithelial cells (IECs) and the tight junctions between them are critical components of the intestinal barrier and are primarily responsible for nutrient absorption. Goblet cells in the epithelial layer secrete mucus that forms an additional barrier of protection. Paneth cells provide supportive functions, including the secretion of antimicrobial peptides and production of growth factors for epithelial stem cells.6

Equally important to the intestinal mucosa are immune cells with multiple functions, including monitoring for pathogens and maintaining immune tolerance to food and commensal antigens.7-10 These immune cells are generally located within 1 of 3 compartments: the epithelium (termed intraepithelial lymphocytes), the lamina propria (termed lamina propria lymphocytes), and specialized intestine-associated lymphoid structures, which include isolated lymphoid follicles, aggregated lymphoid follicles (named Peyer’s patches), and mesenteric lymph nodes.

Community organization of intestinal commensal microorganisms

The human intestinal tracts harbors an estimated 10 trillion bacteria of roughly 1000 species. Approximately 15 000 distinct species of bacteria have been identified in intestinal samples across human populations.11 A simplified guide to the taxonomy of common intestinal bacterial commensals is provided in Table 2. In addition to bacteria, the intestinal tract can also house commensal microbes from the fungi kingdom,12 as well as a variety of viruses with tropism for commensal bacteria13 and host tissues.14

Interactions between the intestinal mucosa and commensal microorganisms

Underdevelopment of the immune system in germ-free animals

With the advent of techniques to generate and maintain germ-free rodents developed in the 1940s,15 it became possible to examine how the microbiota contributes to development of the immune system. In these germ-free animals, the development of systemic immune organs such as the spleen and thymus is not obviously perturbed,16 although changes in neutrophil function, antigen presentation, and natural killer cell licensing have been observed.17,18 In contrast, major changes are seen in intestinal mucosal immunity. In particular, gut-associated lymphoid tissues including isolated lymphoid follicles,19,20 Peyer’s patches, and mesenteric lymph nodes are all severely underdeveloped.21

Improved intestinal barrier function in response to microbial colonization

One response of the intestinal mucosa to colonization by commensal bacteria is to keep the intestinal microbiota safely at bay. In an antigen-specific manner, B cells mature into plasma cells that produce immunoglobulin A (IgA), which is secreted into the gut lumen.22 Epithelial cells can detect bacterial products via innate MyD88-dependent signaling receptors and, as a result, generate antimicrobial peptides such as regenerating islet-derived protein 3-γ (Reg3γ).23 These molecules have local inhibitory or bactericidal properties.24 Finally, goblet cell–derived mucus generates a difficult-to-penetrate barrier, especially in the colon, to separate intestinal commensals from the epithelium.25

Maintaining tolerance to intestinal antigens

Immune responses in the intestinal tract are uniquely tempered to help prevent development of autoimmunity or allergies while still maintaining the ability to protect against potential pathogens.26 This is critically important because the intestinal lumen is rich in foreign antigens derived from nonpathogenic sources, including intestinal commensals and food. Perhaps the best-studied mediators of immune tolerance to luminal antigens are intestinal regulatory T cells.27 These are present at very low levels in the colons of germ-free mice but can be induced by introduction of bacterial members of the class Clostridia28 and genus Bacteroides.29 Interestingly, regulatory T cells in the small intestine are found at approximately normal frequencies in germ-free mice, and appear to be maintained by the presence of dietary antigens.27 The T-cell receptors of colonic regulatory T cells have been demonstrated to recognize antigens derived from specific commensal bacteria.30 RORγt-expressing regulatory T cells in particular play a variety of roles in preventing immune responses against nonpathogenic intestinal antigens, ranging from regulation of T follicular helper cells31 to prevention of Th2-mediated inflammation32 and Th1/Th17-mediated inflammation.33

In addition to regulatory T cells, another immune cell population that has been found to be critical for intestinal mucosal homeostasis is known as innate lymphoid cells (ILCs). ILCs are a recently described group of lymphoid-lineage immune cells that function in an innate fashion without adaptive immune receptors or antigen-specific responses.34 Group 3 ILCs (ILC3s) are tissue-resident cells that produce Th17-family cytokines including interleukin 22 (IL-22); they are most abundant within the intestinal tract and have an important role in maintaining intestinal barrier function.35 In addition, intestinal ILC3s have been shown to express major histocompatibility complex (MHC) class II and are thought to promote tolerance to commensal bacteria, prevent hyperactivation of T cells during enteric infection, and limit intestinal inflammation by presenting commensal antigens to T cells without providing costimulation.36-38

Changes to the intestinal microbiota early in life may have long-term deleterious effects

On birth, the neonate quickly transitions from a nearly sterile environment into a microbe-rich world, and develops, over the course of weeks to months, its own intestinal microbiota.39,40 Clinically, microbiota perturbations during development have been associated with long-term immune consequences. Perhaps the 2 most common causes of an altered microbiota in human children include cesarian delivery and antibiotic exposure early in life. The mode of delivery at birth has been found to have a profound effect on the initial microbiota of newborns,41 with infants delivered by cesarean delivery displaying an altered microbiota composition consisting largely of skin, rather than vaginal flora. Cesarian delivery, in turn, has in epidemiological studies been associated with allergic and inflammatory conditions.42 Similarly, early-life exposure to antibiotics has been associated with subsequent development of allergic conditions,43 inflammatory bowel disease,44 and metabolic disorders such as obesity, which may be immune-related.45 Potential prevention of late effects in individuals who experience microbiota perturbations with bacteriotherapy is now being examined. A pilot study showed that the intestinal microbiota of newborns delivered by cesarian delivery could be enriched for vaginal bacteria by exposure to maternal vaginal fluids at birth.46 Furthermore, mouse models of asthma47 and food allergies48 indicate that introducing cocktails of intestinal commensal bacteria may be clinically beneficial in these and other conditions. Whether the development of a new immune system within the allogeneic HCT recipient could have parallels to immune development in the neonate is an intriguing concept that has yet to be well-explored.

Components and function of the intestinal epithelium in the setting of GVHD

The effects of conditioning and GVHD on various IEC subsets has been examined predominately in murine models; a summary of the current findings is provided in Table 1. IECs are connected by tight junctions that establish a physical barrier between luminal contents and the intestinal lamina propria.49 Structurally, the surface epithelium of the small intestine forms small finger-like projections termed villi, the interiors of which are supplied by the rich vascular and lymphatic network of the lamina propria. The mature enterocytes of the villous epithelium are supplied by epithelial stem and progenitor cells located within adjacent invaginations of the mucosal surface, termed crypts of Lieberkühn. The intestinal stem cells (ISCs) are located at the crypt base and are capable of generating all cell types of the intestinal epithelium. They are thus critical both for intestinal homeostasis and for regeneration after injury. Recent advances in the identification of specific molecular markers of ISCs (such as Olfm4 and Lgr5) and techniques for their examination ex vivo50-52 have facilitated examination of ISC biology, including in the setting of GVHD.

GVHD has long been suspected of damaging the ISC compartment,53,54 but clear data in support of this have been lacking until recently. Immunohistochemistry in mouse small intestine after MHC-mismatched experimental HCT demonstrated a loss of Olfm4+ ISCs after pretransplant irradiation and in recipients of allogeneic T cells.55 Likewise, a loss of Lgr5+ ISCs was demonstrated using transgenic Lgr5 reporter mice in a MHC-matched (minor histocompatibility–antigen mismatched) allogeneic HCT model; this was confirmed by histologic evaluation of ISCs, as determined by crypt-base columnar cell morphology and location in crypts of wild-type mice with GVHD.56 Moreover, it was shown that mouse ISCs can be protected from radiation injury and subsequent GVHD by systemic pretreatment with R-spondin-1, an ISC growth factor and agonist of canonical Wnt signaling.55 Taken together, these studies indicate that injury to ISCs may be an important component of intestinal GVHD pathophysiology, and that strategies to preserve ISCs may be beneficial.

Once damage has occurred in the intestines, an important component of the recovery process is regeneration of the damaged tissue. Recipient-derived IL-22 has been shown to limit the severity of intestinal pathology resulting from GVHD.56 However, this protective IL-22 signaling may be lost in intestinal GVHD as a result of the elimination of intestinal IL-22-producing ILC3s.56 With the hypothesis of restoring this IL-22-dependent regenerative signal, treatment with recombinant IL-22 starting 1 week after experimental MHC-matched allogeneic HCT was found to improve Lgr5+ ISC recovery, intestinal GVHD histopathology, and overall survival.57 Restoration of this IL-22 signal may also be relevant clinically, where ILC3 deficiency after chemotherapy for initial treatment of acute myeloid leukemia was associated with increased risk of developing GVHD after allogeneic HCT.58 Administration of IL-22 along with systemic corticosteroids is now being investigated for initial treatment of lower intestinal GVHD after allogeneic HCT ( NCT02406651). Interestingly, in spite of the possible reduction in ISCs, it has been observed that IECs from patients with acute intestinal GVHD have an increased proliferation index, as assessed by Ki67 staining and reduced telomere length.59 This IEC proliferation may represent a response to intestinal damage, and as each cell division produces an incremental reduction in telomere length, it is possible that intestinal recovery may be limited by replicative exhaustion; alternatively, telomerase expression may be reduced.

In addition to ISCs, small intestinal crypts also contain specialized Paneth cells. The Paneth cells sit at the crypt bases in close proximity to ISCs and produce ISC growth factors.6 In addition, Paneth cells contain large numbers of secretory granules that store a variety of potent antimicrobial molecules with activity against intestinal bacteria.60 Interestingly, an antimicrobial molecule produced by enterocytes, Reg3α, was identified in an unbiased screen for clinical plasma biomarkers of intestinal GVHD61 and was reproducibly found to be predictive of GVHD prognosis when combined with 2 additional plasma biomarkers (TNFR1 and ST2) in a recent large multicenter study.62 Why plasma levels of Reg3α correlate with GVHD severity remains an open question, but it may either reflect epithelial cell damage or be a physiological response to intestinal injury and compromised barrier function. Although production of Reg3α and its murine homolog Reg3γ have previously been attributed to Paneth cells, it is clear that other non-Paneth-cell IECs produce Reg3γ after experimental HCT in mice.57,63 This potentially explains how Reg3 levels can be elevated despite the loss of Paneth cells that has been observed in the settings of experimental57,64,65 and clinical66 GVHD. Importantly, loss of Paneth cells was found to be a poor prognostic finding in clinical cases of intestinal GVHD.66 In addition to GVHD, reductions in Paneth cell frequency have been observed in mouse models in response to treatment with interferon-γ,67,68 a cytokine with a heavily investigated complex pathophysiology in the setting of allogeneic HCT.69-71 In contrast to Paneth cell deficiency, the cytokine IL-33 was recently reported to promote Paneth cell differentiation.72 IL-33 and its receptor ST2 appear to both play important roles in several aspects of GVHD pathophysiology that are highly context-dependent.73-75

Components and functions of the intestinal immune system in the setting of acute GVHD

Several arms of the immune system play roles in modulating intestinal inflammation during acute GVHD. Neutrophil infiltration in the small intestine in response to translocation of commensal bacteria or their products has been reported to contribute to development of GVHD via production of reactive oxygen species, which leads to aggravated tissue damage.76 As noted earlier, IL-22-producing ILC3s have been shown to be severely reduced in the setting of GVHD.56 Antigen-presenting cells are another immune population that contributes to intestinal GVHD severity by directing T cells to differentiate and become activated.77 Dendritic cells from mesenteric lymph nodes have been shown to induce T-cell homing to the intestines and focal intestinal damage.78,79 Another myeloid population, intestinal monocytes, was found in the setting of GVHD to promote Th17 differentiation,80 which is important for recruitment of neutrophils and macrophages to sites of inflammation.

Several groups have found that Th17 differentiation may be an important contributor to intestinal GVHD.81 More recently, analysis of target organ tissues at the time of GVHD diagnosis also indicated that Th17 differentiation and STAT3 signaling are prominent in cases of severe GVHD.82,83 The cytokine IL-6, which acts upstream to induce Th17 differentiation, has also been identified as a potential target to prevent GVHD in murine models.84,85 Tocilizumab, a monoclonal antibody antagonist of the IL-6 receptor that is approved for the treatment of rheumatoid arthritis, produced promising results as a GVHD-prophylaxis agent in a single-arm phase 1/2 study.86 Additional clinical trials with tocilizumab in allogeneic HCT recipients are ongoing ( NCT02206035, NCT02057770, NCT02447055). Interestingly, in addition to the T-helper cells described earlier, effector CD8 cells can also undergo Th17-like differentiation and contribute to GVHD,87 and IL-6 also is a key agent in directing this type of effector differentiation.88

In addition to T cells, the B-cell group of the mucosal immune system is also perturbed in the setting of GVHD. Reduced IgA levels in the intestinal lumen of mice can be seen after HCT64 and in the serum of patients during the first 6 months after HCT. Those who develop acute or chronic GVHD can remain chronically IgA-deficient.89 Whether decreases in IgA levels or genetic IgA deficiency of the donor or host can contribute to GVHD pathophysiology has not, to our knowledge, been thoroughly investigated.

Commensal aspects of the intestinal mucosa in GVHD

Changes to intestinal bacteria in the setting of GVHD

Development of GVHD can lead to significant changes in intestinal microbiota composition. GVHD in both mice11,30,35 and humans30,40,41 is associated with loss of intestinal bacterial diversity and an expansion of 2 groups of bacteria: Gram-negative Enterobacteriales (including Escherichia, Klebsiella, and Enterobacter species) and Gram-positive Lactobacillales (including Lactobacillus, Enterococcus, and Streptococcus species). This expansion is coupled with loss of obligately anaerobic Gram-positive bacteria including Clostridia.64-65,90 Reasons why acute GVHD leads to changes in bacterial flora composition are unclear. The mechanisms of this a matter of speculation, but some possibilities include reductions in oral nutritional intake that accompany development of GVHD, changes in dietary behavior or preferences by patients, effects of oral medications, disruption of the production of antimicrobial peptides by intestinal epithelial cells, changes in bile acid metabolism or secretion, or changes in gut transit time in the setting of diarrhea.

A potential consequence of acute GVHD-associated changes in intestinal bacterial composition could be alterations in the metabolites produced by these bacteria. Interestingly, in accordance with this hypothesis, a recent study reported that unbiased profiling of bacterial metabolites identified butyrate as significantly depleted in the intestinal tissues of mice with acute GVHD.91 Butyrate is a short-chain fatty acid produced by members of the intestinal microbiota and is known to induce regulatory T cells.92,93 Butyrate can inhibit histone deacetylases, and intestinal epithelial cells exhibited reduced histone acetylation in the setting of acute GVHD. Oral feeding with butyrate or, alternatively, introduction of a mixture of butyrate-producing Clostridia led to restoration of intestinal epithelial histone acetylation and improved survival in mice with acute GVHD. Clinical strategies to increase intestinal butyrate levels are in active development. For example, preclinical evidence suggests potato-based starches can induce production of butyrate from the microbiota,94 and a randomized trial of this prebiotic for acute GVHD prevention is underway ( NCT02763033).

Separate from the development of acute GVHD in which alloreactive T cells mount an immune response against host tissues, other clinical developments during HCT can lead to major changes in intestinal bacteria.95 Administration of antibiotics during the HCT hospitalization explains the majority of these changes, frequently in the form of prophylactic antibiotics or empiric antibiotics for neutropenic fever. The choice of antibiotic can determine the degree of microbiota disruption, and agents with more limited spectra of activity appear to be associated with reduced acute GVHD severity.96,97 For example, rifaximin was recently reported to perform favorably as bacterial prophylaxis in comparison with a historical cohort treated with a prophylactic combination of ciprofloxacin and metronidazole.97 Rifaximin use was associated with both better preservation of intestinal commensal bacteria and reduced transplant-related mortality. Similarly, antibiotics used to treat neutropenic fever that spare obligate anaerobes, including cefepime and aztreonam, produce less perturbation to intestinal bacterial composition compared with broader-spectrum antibiotics with increased anaerobic activity such as piperacillin-tazobactam and carbapenems.96 Use of narrow-spectrum antibiotics was associated with reduced acute GVHD lethality in humans and reduced acute GVHD severity in animal models. Prospective studies exploring different antibiotic regimens for prevention or treatment of neutropenic infections while minimizing intestinal bacterial repercussions are now beginning to be investigated ( NCT02641236).

How intestinal bacteria can modulate acute GVHD severity remains an open question. As noted earlier, early murine studies from the 1970s with mice transplanted in germ-free conditions1 or while receiving gut-decontaminating antibiotics,2 as well as clinical studies based on these findings,98-100 suggested that intestinal microbes, as a whole, contribute to development of acute GVHD. Potentially proinflammatory commensal bacteria include Enterobacteriales and Enterococcus in both murine65,64 and clinical101,102 acute GVHD. Other intestinal bacterial populations, however, appear to help reduce acute GVHD, including Lactobacillus64,103 and Clostridia.91,104-106 Thus far, identification of specific individual bacteria, or consortia of bacteria, that are important for ameliorating GVHD has not been accomplished but is an active area of investigation. Concurrently, clinical trials in which patients receiving allogeneic HCT are being treated with introduction of a complete intestinal microbiome are actively enrolling. Strategies include autologous fecal microbiota transplantation using a patient’s own personal microbiome that was collected and preserved pre-HCT ( NCT02269150), as well as introduction of a third-party intestinal microbiome donated by a healthy volunteer that can be introduced to patients in the form of capsules ( NCT02733744). Notably, both of these approaches have already been shown to be beneficial for the treatment of Clostridium difficile infection, a disease that is closely associated with antibiotic-related intestinal microbiota disruption.107,108

A growing body of literature has highlighted the importance of the mucus layer as a critical line of defense in the intestinal mucosa.109 Produced and secreted by goblet cells, mucus forms a molecular network that concentrates epithelial-derived antimicrobial molecules in the intestinal lumen adjacent to the epithelium and, particularly in the colon, also generates a dense physical barrier that is difficult for most intestinal bacteria to penetrate.110 The building block of intestinal mucus is the glycoprotein MUC2, a rich source of carbohydrates. MUC2 is continuously secreted by goblet cells as well as consumed by intestinal bacteria, which harbor enzymes that allow metabolism of MUC2 glycans. Loss of the mucus layer was recently observed in mice with acute GVHD aggravated by broad-spectrum antibiotics, indicating that changes in intestinal bacterial composition can have an effect on the health and integrity of the mucus layer.96 Clinical evidence suggests the mucus layer can, in turn, shape the composition of the intestinal microbiota. Fucosylation of mucus glycans can vary between individuals, which is predominately determined by the function of the fucosyltransferase FUT2. Polymorphisms of the FUT2 gene are common and result in 2 different phenotypes, including so-called secretors and nonsecretors. Interestingly, nonsecretors have been found to harbor intestinal microbiota with reduced species richness,111 and nonsecretor status in a study of 150 patients was found to be associated with a decreased risk for acute GVHD, but an increased risk for bacteremia after allogenic HSCT.112

Interactions between bacterial and fungal commensals within the intestinal tract are also beginning to be uncovered. Commensal bacteria, including Clostridia and Bacteroides, are important for preventing overgrowth of Candida in the intestinal tract.113 Heat-killed Candida albicans, as well as purified α-mannan, a major component of fungal cell wall, can aggravate acute GVHD in mouse models.114 In addition, pharmacologic inhibition of Candida in the form of fluconazole was found to reduce acute GVHD in a randomized, placebo-controlled study of prophylaxis of invasive candidiasis.115 Candida colonization has also been found to be associated with increased acute GVHD, although the interaction may have an extra layer of complexity, as the association was only observed in the subset of patients with a wild-type dectin-1 genotype. Patients lacking wild-type dectin-1, an innate pattern receptor that can recognize Candida, did not show an association between candida colonization and acute GVHD.116

Finally, a potential link between enteric viruses and acute intestinal GVHD has been recognized for some time. CMV reactivation after allogeneic HCT has been found to be associated with an increased risk of developing acute GVHD,117 raising the possibility that CMV replication may contribute to allogeneic T-cell activation. This may also be true for other viruses with potential tropism for intestinal epithelium; a recent report found that, using a panel of PCR assays against enteric viruses, intestinal virus positivity before allogeneic HCT was associated with later development of acute GVHD.14 Interestingly, the vast majority of virions in the intestinal tract are nonpathogenic bacteriophages that can only infect and replicate within bacteria. Specific changes, however, in the profile of these bacteriophages have been observed in patients with ulcerative colitis, which in turn are distinct from those found in patients with Crohn’s disease.118 This raises the possibility that perturbations in both the nonpathogenic and pathogenic subsets of the intestinal virome may also be linked with intestinal GVHD.

Future strategies

Recent work has resulted in a renewed appreciation for the bidirectional relationship that exists between the intestinal mucosa and intestinal commensals, which can directly have an effect on the development and maintenance of acute intestinal GVHD. As new tools to characterize the intestinal mucosa and the intestinal microbiota become available, we will come closer to a time when manipulation of the interactions between intestinal microbiota, host tissues, and immune function can be incorporated into the care of patients.

Alan Hanash, Adult Bone Marrow Transplantation Service, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY 10065; e-mail:; and Robert Jenq, Adult Bone Marrow Transplantation Service, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY 10065; e-mail:


  • Off-label drug use: None disclosed.
  • Conflict-of-interest disclosures: J.U.P. holds patents with or receives royalties from Seres Therapeutics, Inc. A.M.H. holds patents filed for use of interleukin 22 as a treatment of GVHD. R.R.J. is on the board of directors or an advisory committee for Seres Therapeutics, Inc.; has consulted for Ziopharm Oncology; and holds patents with or receives royalties from Seres Therapeutics, Inc.


1. Jones JM, Wilson R, Bealmear PM. Mortality and gross pathology of secondary disease in germfree mouse radiation chimeras. Radiat Res. 1971;45(3):577-588.

2. van Bekkum DW, Roodenburg J, Heidt PJ, van der Waaij D. Mitigation of secondary disease of allogeneic mouse radiation chimeras by modification of the intestinal microflora. J Natl Cancer Inst. 1974;52(2):401-404.

3. Teshima T, Reddy P, Zeiser R. Acute graft-versus-host disease: novel biological insights. Biol Blood Marrow Transplant. 2016;22(1):11-16.

4. Morgan XC, Huttenhower C. Meta’omic analytic techniques for studying the intestinal microbiome. Gastroenterology. 2014;146(6):1437-1448.

5. Luissint AC, Parkos CA, Nusrat A. Inflammation and the intestinal barrier: leukocyte-epithelial cell interactions, cell junction remodeling, and mucosal repair. Gastroenterology. 2016;151(4):616-632.

6. Sato T, van Es JH, Snippert HJ, et al. Paneth cells constitute the niche for Lgr5 stem cells in intestinal crypts. Nature. 2011;469(7330):415-418.

7. Markey KA, MacDonald KP, Hill GR. The biology of graft-versus-host disease: experimental systems instructing clinical practice. Blood. 2014;124(3):354-362.

8. Blazar BR, Murphy WJ, Abedi M. Advances in graft-versus-host disease biology and therapy. Nat Rev Immunol. 2012;12(6):443-458.

9. Stenger EO, Turnquist HR, Mapara MY, Thomson AW. Dendritic cells and regulation of graft-versus-host disease and graft-versus-leukemia activity. Blood. 2012;119(22):5088-5103.

10. Shlomchik WD. Graft-versus-host disease. Nat Rev Immunol. 2007;7(5):340-352.

11. Murphy S, Nguyen VH. Role of gut microbiota in graft-versus-host disease. Leuk Lymphoma. 2011;52(10):1844-1856.

12. Underhill DM, Iliev ID. The mycobiota: interactions between commensal fungi and the host immune system. Nat Rev Immunol. 2014;14(6):405-416.

13. Pfeiffer JK, Virgin HW. Viral immunity. Transkingdom control of viral infection and immunity in the mammalian intestine. Science. 2016;351(6270):239.

14. van Montfrans J, Schulz L, Versluys B, et al. Viral PCR positivity in stool before allogeneic hematopoietic cell transplantation is strongly associated with acute intestinal graft-versus-host disease. Biol Blood Marrow Transplant. 2015;21(4):772-774.

15. Reyniers JA, Trexler PC, Ervin RF. Rearing germ-free albino rats. Lobund Rep. 1946(1):1-84.

16. Bauer H, Horowitz RE, Levenson SM, Popper H. The response of the lymphatic tissue to the microbial flora. Studies on germfree mice. Am J Pathol. 1963;42:471-483.

17. Belkaid Y, Hand TW. Role of the microbiota in immunity and inflammation. Cell. 2014;157(1):121-141.

18. Wu HJ, Wu E. The role of gut microbiota in immune homeostasis and autoimmunity. Gut Microbes. 2012;3(1):4-14.

19. Pabst O, Herbrand H, Friedrichsen M, et al. Adaptation of solitary intestinal lymphoid tissue in response to microbiota and chemokine receptor CCR7 signaling. J Immunol. 2006;177(10):6824-6832.

20. Lorenz RG, Chaplin DD, McDonald KG, McDonough JS, Newberry RD. Isolated lymphoid follicle formation is inducible and dependent upon lymphotoxin-sufficient B lymphocytes, lymphotoxin beta receptor, and TNF receptor I function. J Immunol. 2003;170(11):5475-5482.

21. St?pánková R, Kovár? F, Kruml J. Lymphatic tissue of the intestinal tract of germfree and conventional rabbits. Folia Microbiol (Praha). 1980;25(6):491-495.

22. Mirpuri J, Raetz M, Sturge CR, et al. Proteobacteria-specific IgA regulates maturation of the intestinal microbiota. Gut Microbes. 2014;5(1):28-39.

23. Vaishnava S, Yamamoto M, Severson KM, et al. The antibacterial lectin RegIIIgamma promotes the spatial segregation of microbiota and host in the intestine. Science. 2011;334(6053):255-258.

24. Cash HL, Whitham CV, Behrendt CL, Hooper LV. Symbiotic bacteria direct expression of an intestinal bactericidal lectin. Science. 2006;313(5790):1126-1130.

25. Petersson J, Schreiber O, Hansson GC, et al. Importance and regulation of the colonic mucus barrier in a mouse model of colitis. Am J Physiol Gastrointest Liver Physiol. 2011;300(2):G327-G333.

26. Mowat AM. Anatomical basis of tolerance and immunity to intestinal antigens. Nat Rev Immunol. 2003;3(4):331-341.

27. Kim KS, Hong SW, Han D, et al. Dietary antigens limit mucosal immunity by inducing regulatory T cells in the small intestine. Science. 2016;351(6275):858-863.

28. Atarashi K, Tanoue T, Oshima K, et al. Treg induction by a rationally selected mixture of Clostridia strains from the human microbiota. Nature. 2013;500(7461):232-236.

29. Faith JJ, Ahern PP, Ridaura VK, Cheng J, Gordon JI. Identifying gut microbe-host phenotype relationships using combinatorial communities in gnotobiotic mice. Sci Transl Med. 2014;6(220):220ra11.

30. Lathrop SK, Bloom SM, Rao SM, et al. Peripheral education of the immune system by colonic commensal microbiota. Nature. 2011;478(7368):250-254.

31. Kawamoto S, Maruya M, Kato LM, et al. Foxp3(+) T cells regulate immunoglobulin a selection and facilitate diversification of bacterial species responsible for immune homeostasis. Immunity. 2014;41(1):152-165.

32. Ohnmacht C, Park JH, Cording S, et al. Mucosal immunology. The microbiota regulates type 2 immunity through RORγt? T cells. Science. 2015;349(6251):989-993.

33. Sefik E, Geva-Zatorsky N, Oh S, et al. Mucosal immunology. Individual intestinal symbionts induce a distinct population of RORγ? regulatory T cells. Science. 2015;349(6251):993-997.

34. Spits H, Artis D, Colonna M, et al. Innate lymphoid cells--a proposal for uniform nomenclature. Nat Rev Immunol. 2013;13(2):145-149.

35. Klose CS, Artis D. Innate lymphoid cells as regulators of immunity, inflammation and tissue homeostasis. Nat Immunol. 2016;17(7):765-774.

36. Wagage S, Harms Pritchard G, Dawson L, Buza EL, Sonnenberg GF, Hunter CA. The group 3 innate lymphoid cell defect in aryl hydrocarbon receptor deficient mice is associated with T cell hyperactivation during intestinal infection. PLoS One. 2015;10(5):e0128335.

37. Mackley EC, Houston S, Marriott CL, et al. CCR7-dependent trafficking of RORγ? ILCs creates a unique microenvironment within mucosal draining lymph nodes. Nat Commun. 2015;6:5862.

38. Hepworth MR, Monticelli LA, Fung TC, et al. Innate lymphoid cells regulate CD4+ T-cell responses to intestinal commensal bacteria. Nature. 2013;498(7452):113-117.

39. Gensollen T, Iyer SS, Kasper DL, Blumberg RS. How colonization by microbiota in early life shapes the immune system. Science. 2016;352(6285):539-544.

40. Mueller NT, Bakacs E, Combellick J, Grigoryan Z, Dominguez-Bello MG. The infant microbiome development: mom matters. Trends Mol Med. 2015;21(2):109-117.

41. Dominguez-Bello MG, Costello EK, Contreras M, et al. Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns. Proc Natl Acad Sci USA. 2010;107(26):11971-11975.

42. Sevelsted A, Stokholm J, Bønnelykke K, Bisgaard H. Cesarean section and chronic immune disorders. Pediatrics. 2015;135(1):e92-e98.

43. Kuo CH, Kuo HF, Huang CH, Yang SN, Lee MS, Hung CH. Early life exposure to antibiotics and the risk of childhood allergic diseases: an update from the perspective of the hygiene hypothesis. J Microbiol Immunol Infect. 2013;46(5):320-329.

44. Shaw SY, Blanchard JF, Bernstein CN. Association between the use of antibiotics in the first year of life and pediatric inflammatory bowel disease. Am J Gastroenterol. 2010;105(12):2687-2692.

45. Cox LM, Yamanishi S, Sohn J, et al. Altering the intestinal microbiota during a critical developmental window has lasting metabolic consequences. Cell. 2014;158(4):705-721.

46. Dominguez-Bello MG, De Jesus-Laboy KM, Shen N, et al. Partial restoration of the microbiota of cesarean-born infants via vaginal microbial transfer. Nat Med. 2016;22(3):250-253.

47. Arrieta MC, Stiemsma LT, Dimitriu PA, et al; CHILD Study Investigators. Early infancy microbial and metabolic alterations affect risk of childhood asthma. Sci Transl Med. 2015;7(307):307ra152.

48. Stefka AT, Feehley T, Tripathi P, et al. Commensal bacteria protect against food allergen sensitization. Proc Natl Acad Sci USA. 2014;111(36):13145-13150.

49. Jenq RR, Taur Y, Devlin SM, et al. Intestinal Blautia is associated with reduced death from graft-versus-host disease. Biol Blood Marrow Transplant. 2015;21(8):1373-1383.

50. Sato T, Vries RG, Snippert HJ, et al. Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature. 2009;459(7244):262-265.

51. van der Flier LG, Haegebarth A, Stange DE, van de Wetering M, Clevers H. OLFM4 is a robust marker for stem cells in human intestine and marks a subset of colorectal cancer cells. Gastroenterology. 2009;137(1):15-17.

52. Barker N, van Es JH, Kuipers J, et al. Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature. 2007;449(7165):1003-1007.

53. Sale GE. Does graft-versus-host disease attack epithelial stem cells? Mol Med Today. 1996;2(3):114-119.

54. Epstein RJ, McDonald GB, Sale GE, Shulman HM, Thomas ED. The diagnostic accuracy of the rectal biopsy in acute graft-versus-host disease: a prospective study of thirteen patients. Gastroenterology. 1980;78(4):764-771.

55. Takashima S, Kadowaki M, Aoyama K, et al. The Wnt agonist R-spondin1 regulates systemic graft-versus-host disease by protecting intestinal stem cells. J Exp Med. 2011;208(2):285-294.

56. Hanash AM, Dudakov JA, Hua G, et al. Interleukin-22 protects intestinal stem cells from immune-mediated tissue damage and regulates sensitivity to graft versus host disease. Immunity. 2012;37(2):339-350.

57. Lindemans CA, Calafiore M, Mertelsmann AM, et al. Interleukin-22 promotes intestinal-stem-cell-mediated epithelial regeneration. Nature. 2015;528(7583):560-564.

58. Munneke JM, Björklund AT, Mjösberg JM, et al. Activated innate lymphoid cells are associated with a reduced susceptibility to graft-versus-host disease. Blood. 2014;124(5):812-821.

59. Hummel S, Ventura Ferreira MS, Heudobler D, et al. Telomere shortening in enterocytes of patients with uncontrolled acute intestinal graft-versus-host disease. Blood. 2015;126(22):2518-2521.

60. Peterson LW, Artis D. Intestinal epithelial cells: regulators of barrier function and immune homeostasis. Nat Rev Immunol. 2014;14(3):141-153.

61. Ferrara JL, Harris AC, Greenson JK, et al. Regenerating islet-derived 3-alpha is a biomarker of gastrointestinal graft-versus-host disease. Blood. 2011;118(25):6702-6708.

62. Levine JE, Braun TM, Harris AC, et al; Blood and Marrow Transplant Clinical Trials Network. A prognostic score for acute graft-versus-host disease based on biomarkers: a multicentre study. Lancet Haematol. 2015;2(1):e21-e29.

63. Eriguchi Y, Uryu H, Nakamura K, et al. Reciprocal expression of enteric antimicrobial proteins in intestinal graft-versus-host disease. Biol Blood Marrow Transplant. 2013;19(10):1525-1529.

64. Jenq RR, Ubeda C, Taur Y, et al. Regulation of intestinal inflammation by microbiota following allogeneic bone marrow transplantation. J Exp Med. 2012;209(5):903-911.

65. Eriguchi Y, Takashima S, Oka H, et al. Graft-versus-host disease disrupts intestinal microbial ecology by inhibiting Paneth cell production of α-defensins. Blood. 2012;120(1):223-231.

66. Levine JE, Huber E, Hammer ST, et al. Low Paneth cell numbers at onset of gastrointestinal graft-versus-host disease identify patients at high risk for nonrelapse mortality. Blood. 2013;122(8):1505-1509.

67. Farin HF, Karthaus WR, Kujala P, et al. Paneth cell extrusion and release of antimicrobial products is directly controlled by immune cell-derived IFN-γ. J Exp Med. 2014;211(7):1393-1405.

68. Raetz M, Hwang SH, Wilhelm CL, et al. Parasite-induced TH1 cells and intestinal dysbiosis cooperate in IFN-γ-dependent elimination of Paneth cells. Nat Immunol. 2013;14(2):136-142.

69. Wang H, Yang YG. The complex and central role of interferon-γ in graft-versus-host disease and graft-versus-tumor activity. Immunol Rev. 2014;258(1):30-44.

70. Robb RJ, Hill GR. The interferon-dependent orchestration of innate and adaptive immunity after transplantation. Blood. 2012;119(23):5351-5358.

71. Lu Y, Waller EK. Dichotomous role of interferon-gamma in allogeneic bone marrow transplant. Biol Blood Marrow Transplant. 2009;15(11):1347-1353.

72. Mahapatro M, Foersch S, Hefele M, et al. Programming of intestinal epithelial differentiation by IL-33 derived from pericryptal fibroblasts in response to systemic infection. Cell Reports. 2016;15(8):1743-1756.

73. Matta BM, Reichenbach DK, Zhang X, et al. Peri-alloHCT IL-33 administration expands recipient T-regulatory cells that protect mice against acute GVHD. Blood. 2016;128(3):427-439.

74. Reichenbach DK, Schwarze V, Matta BM, et al. The IL-33/ST2 axis augments effector T-cell responses during acute GVHD. Blood. 2015;125(20):3183-3192.

75. Zhang J, Ramadan AM, Griesenauer B, et al. ST2 blockade reduces sST2-producing T cells while maintaining protective mST2-expressing T cells during graft-versus-host disease. Sci Transl Med. 2015;7(308):308ra160.

76. Schwab L, Goroncy L, Palaniyandi S, et al. Neutrophil granulocytes recruited upon translocation of intestinal bacteria enhance graft-versus-host disease via tissue damage. Nat Med. 2014;20(6):648-654.

77. MacDonald KP, Shlomchik WD, Reddy P. Biology of graft-versus-host responses: recent insights. Biol Blood Marrow Transplant. 2013;19(suppl 1):S10-S14.

78. Koyama M, Cheong M, Markey KA, et al. Donor colonic CD103+ dendritic cells determine the severity of acute graft-versus-host disease. J Exp Med. 2015;212(8):1303-1321.

79. Kim TD, Terwey TH, Zakrzewski JL, et al. Organ-derived dendritic cells have differential effects on alloreactive T cells. Blood. 2008;111(5):2929-2940.

80. Reinhardt K, Foell D, Vogl T, et al. Monocyte-induced development of Th17 cells and the release of S100 proteins are involved in the pathogenesis of graft-versus-host disease. J Immunol. 2014;193(7):3355-3365.

81. van der Waart AB, van der Velden WJ, Blijlevens NM, Dolstra H. Targeting the IL17 pathway for the prevention of graft-versus-host disease. Biol Blood Marrow Transplant. 2014;20(6):752-759.

82. Ratajczak P, Janin A, Peffault de Latour R, et al. Th17/Treg ratio in human graft-versus-host disease. Blood. 2010;116(7):1165-1171.

83. Betts BC, Sagatys EM, Veerapathran A, et al. CD4+ T cell STAT3 phosphorylation precedes acute GVHD, and subsequent Th17 tissue invasion correlates with GVHD severity and therapeutic response. J Leukoc Biol. 2015;97(4):807-819.

84. Tawara I, Koyama M, Liu C, et al. Interleukin-6 modulates graft-versus-host responses after experimental allogeneic bone marrow transplantation. Clin Cancer Res. 2011;17(1):77-88.

85. Varelias A, Gartlan KH, Kreijveld E, et al. Lung parenchyma-derived IL-6 promotes IL-17A-dependent acute lung injury after allogeneic stem cell transplantation. Blood. 2015;125(15):2435-2444.

86. Kennedy GA, Varelias A, Vuckovic S, et al. Addition of interleukin-6 inhibition with tocilizumab to standard graft-versus-host disease prophylaxis after allogeneic stem-cell transplantation: a phase 1/2 trial. Lancet Oncol. 2014;15(13):1451-1459.

87. Gartlan KH, Markey KA, Varelias A, et al. Tc17 cells are a proinflammatory, plastic lineage of pathogenic CD8+ T cells that induce GVHD without antileukemic effects. Blood. 2015;126(13):1609-1620.

88. Tajima M, Wakita D, Noguchi D, et al. IL-6-dependent spontaneous proliferation is required for the induction of colitogenic IL-17-producing CD8+ T cells. J Exp Med. 2008;205(5):1019-1027.

89. Abedi MR, Hammarström L, Ringdén O, Smith CI. Development of IgA deficiency after bone marrow transplantation. The influence of acute and chronic graft-versus-host disease. Transplantation. 1990;50(3):415-421.

90. Heimesaat MM, Nogai A, Bereswill S, et al. MyD88/TLR9 mediated immunopathology and gut microbiota dynamics in a novel murine model of intestinal graft-versus-host disease. Gut. 2010;59(8):1079-1087.

91. Mathewson ND, Jenq R, Mathew AV, et al. Gut microbiome-derived metabolites modulate intestinal epithelial cell damage and mitigate graft-versus-host disease. Nat Immunol. 2016;17(5):505-513.

92. Arpaia N, Campbell C, Fan X, et al. Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature. 2013;504(7480):451-455.

93. Smith PM, Howitt MR, Panikov N, et al. The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science. 2013;341(6145):569-573.

94. Venkataraman A, Sieber JR, Schmidt AW, Waldron C, Theis KR, Schmidt TM. Variable responses of human microbiomes to dietary supplementation with resistant starch. Microbiome. 2016;4(1):33.

95. Taur Y, Xavier JB, Lipuma L, et al. Intestinal domination and the risk of bacteremia in patients undergoing allogeneic hematopoietic stem cell transplantation. Clin Infect Dis. 2012;55(7):905-914.

96. Shono Y, Docampo MD, Peled JU, et al. Increased GVHD-related mortality with broad-spectrum antibiotic use after allogeneic hematopoietic stem cell transplantation in human patients and mice. Sci Transl Med. 2016;8(339):339ra71.

97. Weber D, Oefner PJ, Dettmer K, et al. Rifaximin preserves intestinal microbiota balance in patients undergoing allogeneic stem cell transplantation. Bone Marrow Transplant. 2016;51(8):1087-1092.

98. Storb R, Prentice RL, Buckner CD, et al. Graft-versus-host disease and survival in patients with aplastic anemia treated by marrow grafts from HLA-identical siblings. Beneficial effect of a protective environment. N Engl J Med. 1983;308(6):302-307.

99. Vossen JM, Heidt PJ, van den Berg H, Gerritsen EJ, Hermans J, Dooren LJ. Prevention of infection and graft-versus-host disease by suppression of intestinal microflora in children treated with allogeneic bone marrow transplantation. Eur J Clin Microbiol Infect Dis. 1990;9(1):14-23.

100. Beelen DW, Elmaagacli A, Müller KD, Hirche H, Schaefer UW. Influence of intestinal bacterial decontamination using metronidazole and ciprofloxacin or ciprofloxacin alone on the development of acute graft-versus-host disease after marrow transplantation in patients with hematologic malignancies: final results and long-term follow-up of an open-label prospective randomized trial. Blood. 1999;93(10):3267-3275.

101. Holler E, Butzhammer P, Schmid K, et al. Metagenomic analysis of the stool microbiome in patients receiving allogeneic stem cell transplantation: loss of diversity is associated with use of systemic antibiotics and more pronounced in gastrointestinal graft-versus-host disease. Biol Blood Marrow Transplant. 2014;20(5):640-645.

102. Simms-Waldrip T, Meir M, Fan D, et al. The role of gut microbiota in the development of intestinal GVHD. Biol Blood Marrow Transplant. 2014;20(2):S55-S56.

103. Gerbitz A, Schultz M, Wilke A, et al. Probiotic effects on experimental graft-versus-host disease: let them eat yogurt. Blood. 2004;103(11):4365-4367.

104. Taur Y, Jenq RR, Perales MA, et al. The effects of intestinal tract bacterial diversity on mortality following allogeneic hematopoietic stem cell transplantation. Blood. 2014;124(7):1174-1182.

105. Jenq RR, Taur Y, Devlin SM, et al. Intestinal Blautia is associated with reduced death from graft-versus-host disease. Biol Blood Marrow Transplant. 2015;21(8):1373-1383.

106. Weber D, Oefner PJ, Hiergeist A, et al. Low urinary indoxyl sulfate levels early after transplantation reflect a disrupted microbiome and are associated with poor outcome. Blood. 2015;126(14):1723-1728.

107. Youngster I, Russell GH, Pindar C, Ziv-Baran T, Sauk J, Hohmann EL. Oral, capsulized, frozen fecal microbiota transplantation for relapsing Clostridium difficile infection. JAMA. 2014;312(17):1772-1778.

108. van Nood E, Vrieze A, Nieuwdorp M, et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med. 2013;368(5):407-415.

109. Pelaseyed T, Bergström JH, Gustafsson JK, et al. The mucus and mucins of the goblet cells and enterocytes provide the first defense line of the gastrointestinal tract and interact with the immune system. Immunol Rev. 2014;260(1):8-20.

110. Birchenough GM, Johansson ME, Gustafsson JK, Bergström JH, Hansson GC. New developments in goblet cell mucus secretion and function. Mucosal Immunol. 2015;8(4):712-719.

111. Wacklin P, Tuimala J, Nikkilä J, et al. Faecal microbiota composition in adults is associated with the FUT2 gene determining the secretor status. PLoS One. 2014;9(4):e94863.

112. Rayes A, Morrow AL, Payton LR, Lake KE, Lane A, Davies SM. A genetic modifier of the gut microbiome influences the risk of graft-versus-host disease and bacteremia after hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2016;22(3):418-422.

113. Fan D, Coughlin LA, Neubauer MM, et al. Activation of HIF-1α and LL-37 by commensal bacteria inhibits Candida albicans colonization. Nat Med. 2015;21(7):808-814.

114. Uryu H, Hashimoto D, Kato K, et al. α-Mannan induces Th17-mediated pulmonary graft-versus-host disease in mice. Blood. 2015;125(19):3014-3023.

115. Marr KA, Seidel K, Slavin MA, et al. Prolonged fluconazole prophylaxis is associated with persistent protection against candidiasis-related death in allogeneic marrow transplant recipients: long-term follow-up of a randomized, placebo-controlled trial. Blood. 2000;96(6):2055-2061.

116. van der Velden WJ, Plantinga TS, Feuth T, Donnelly JP, Netea MG, Blijlevens NM. The incidence of acute graft-versus-host disease increases with Candida colonization depending the dectin-1 gene status. Clin Immunol. 2010;136(2):302-306.

117. Cantoni N, Hirsch HH, Khanna N, et al. Evidence for a bidirectional relationship between cytomegalovirus replication and acute graft-versus-host disease. Biol Blood Marrow Transplant. 2010;16(9):1309-1314.

118. Norman JM, Handley SA, Baldridge MT, et al. Disease-specific alterations in the enteric virome in inflammatory bowel disease. Cell. 2015;160(3):447-460.

119. Hill GR, Crawford JM, Cooke KR, Brinson YS, Pan L, Ferrara JL. Total body irradiation and acute graft-versus-host disease: the role of gastrointestinal damage and inflammatory cytokines. Blood. 1997;90(8):3204-3213.

120. McDole JR, Wheeler LW, McDonald KG, et al. Goblet cells deliver luminal antigen to CD103+ dendritic cells in the small intestine. Nature. 2012;483(7389):345-349.

121. von Moltke J, Ji M, Liang HE, Locksley RM. Tuft-cell-derived IL-25 regulates an intestinal ILC2-epithelial response circuit. Nature. 2016;529(7585):221-225.

122. Becciolini A, Balzi M, Fabbrica D, Potten CS. The effects of irradiation at different times of the day on rat intestinal goblet cells. Cell Prolif. 1997;30(3-4):161-170.

123. Becciolini A, Fabbrica D, Cremonini D, Balzi M. Quantitative changes in the goblet cells of the rat small intestine after irradiation. Acta Radiol Oncol. 1985;24(3):291-299.

124. Levy DA, Wefald A. Gut mucosal mast cells and goblet cells during acute graft-versus-host disease in rats. Ann Inst Pasteur Immunol. 1986;137D(2):281-288.

125. Gorbunov NV, Garrison BR, Kiang JG. Response of crypt Paneth cells in the small intestine following total-body gamma-irradiation. Int J Immunopathol Pharmacol. 2010;23(4):1111-1123.

126. Hubbard-Lucey VM, Shono Y, Maurer K, et al. Autophagy gene Atg16L1 prevents lethal T cell alloreactivity mediated by dendritic cells. Immunity. 2014;41(4):579-591.

Torna all'indice