How to Make an Immune System and a Foreign Host Quickly Cohabit in Peace? The Challenge of Acute Graft-Versus-Host Disease Prevention After Allogeneic Hematopoietic Cell Transplantation.
[en] Allogeneic hematopoietic cell transplantation (alloHCT) has been used as cellular immunotherapy against hematological cancers for more than six decades. Its therapeutic efficacy relies on the cytoreductive effects of the conditioning regimen but also on potent graft-versus-tumor (GVT) reactions mediated by donor-derived immune cells. However, beneficial GVT effects may be counterbalanced by acute GVHD (aGVHD), a systemic syndrome in which donor immune cells attack healthy tissues of the recipient, resulting in severe inflammatory lesions mainly of the skin, gut, and liver. Despite standard prophylaxis regimens, aGVHD still occurs in approximately 20-50% of alloHCT recipients and remains a leading cause of transplant-related mortality. Over the past two decades, advances in the understanding its pathophysiology have helped to redefine aGVHD reactions and clinical presentations as well as developing novel strategies to optimize its prevention. In this review, we provide a brief overview of current knowledge on aGVHD immunopathology and discuss current approaches and novel strategies being developed and evaluated in clinical trials for aGVHD prevention. Optimal prophylaxis of aGVHD would prevent the development of clinically significant aGVHD, while preserving sufficient immune responsiveness to maintain beneficial GVT effects and immune defenses against pathogens.
How to Make an Immune System and a Foreign Host Quickly Cohabit in Peace? The Challenge of Acute Graft-Versus-Host Disease Prevention After Allogeneic Hematopoietic Cell Transplantation.
Publication date :
21 October 2020
Journal title :
Frontiers in Immunology
eISSN :
1664-3224
Publisher :
Frontiers Research Foundation, Lausanne, Switzerland
Duarte RF, Labopin M, Bader P, Basak GW, Bonini C, Chabannon C, et al. Indications for haematopoietic stem cell transplantation for haematological diseases, solid tumours and immune disorders: current practice in Europe. Bone Marrow Transplant (2019) 54(10):1525–52. doi: 10.1038/s41409-019-0516-2
Passweg JR, Baldomero H, Chabannon C, Basak GW, Corbacioglu S, Duarte R, et al. The EBMT activity survey on hematopoietic-cell transplantation and cellular therapy 2018: CAR-T’s come into focus. Bone Marrow Transplant (2020) 55(8):1604–13. doi: 10.1038/s41409-020-0826-4
Filipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, Lee SJ, et al. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. Diagnosis and Staging Working Group Report. Biol Blood Marrow Transplant (2005) 11(12):945–56. doi: 10.1016/j.bbmt.2005.09.004
Jagasia MH, Greinix HT, Arora M, Williams KM, Wolff D, Cowen EW, et al. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. The 2014 Diagnosis and Staging Working Group Report. Biol Blood Marrow Transplant (2015) 21(3):389–401. doi: 10.1016/j.bbmt.2015.02.025
Schoemans HM, Lee SJ, Ferrara JL, Wolff D, Levine JE, Schultz KR, et al. EBMT–NIH–CIBMTR Task Force position statement on standardized terminology & guidance for graft-versus-host disease assessment. Bone Marrow Transplant (2018) 53(11):1401–15. doi: 10.1038/s41409-018-0204-7
Zeiser R, Blazar BR. Acute Graft-versus-Host Disease — Biologic Process, Prevention, and Therapy. Longo DL, editor. N Engl J Med (2017) 377(22):2167–79. doi: 10.1056/NEJMra1609337
Jagasia M, Arora M, Flowers MED, Chao NJ, McCarthy PL, Cutler CS, et al. Risk factors for acute GVHD and survival after hematopoietic cell transplantation. Blood (2012) 119(1):296–307. doi: 10.1182/blood-2011-06-364265
Harris AC, Young R, Devine S, Hogan WJ, Ayuk F, Bunworasate U, et al. International, Multicenter Standardization of Acute Graft-versus-Host Disease Clinical Data Collection: A Report from the Mount Sinai Acute GVHD International Consortium. Biol Blood Marrow Transplant (2016) 22(1):4–10. doi: 10.1016/j.bbmt.2015.09.001
Glucksberg H, Storb R, Fefer A, Buckner CD, Neiman PE, Clift RA, et al. Clinical manifestations of graft-versus-host disease in human recipients of marrow from hl-a-matched sibling donor,s. Transplantation (1974) 18(4):295–304. doi: 10.1097/00007890-197410000-00001
Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J, et al. 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant (1995) 15(6):825–8.
Rowlings PA, Przepiorka D, Klein JP, Gale RP, Passweg JR, Jean Henslee-Downey P, et al. IBMTR Severity index for grading acute graft-versus-host disease: retrospective comparison with glucksberg grade. Br J Haematol (1997) 97(4):855–64. doi: 10.1046/j.1365-2141.1997.1112925.x
Schoemans HM, Goris K, Van Durm R, Fieuws S, De Geest S, Pavletic SZ, et al. The eGVHD App has the potential to improve the accuracy of graft-versus-host disease assessment: a multicenter randomized controlled trial. Haematologica (2018) 103(10):1698–707. doi: 10.3324/haematol.2018.190777
Schoemans HM, Goris K, Van Durm R, Vanbrabant K, De Geest S, Maertens J, et al. Accuracy and usability of the eGVHD app in assessing the severity of graft-versus-host disease at the 2017 EBMT annual congress. Bone Marrow Transplant (2018) 53(4):490–4. doi: 10.1038/s41409-017-0017-0
Clave E, Busson M, Douay C, Peffault de Latour R, Berrou J, Rabian C, et al. Acute graft-versus-host disease transiently impairs thymic output in young patients after allogeneic hematopoietic stem cell transplantation. Blood (2009) 113(25):6477–84. doi: 10.1182/blood-2008-09-176594
Castermans E, Hannon M, Dutrieux J, Humblet-Baron S, Seidel L, Cheynier R, et al. Thymic recovery after allogeneic hematopoietic cell transplantation with non-myeloablative conditioning is limited to patients younger than 60 years of age. Haematologica (2011) 96(2):298–306. doi: 10.3324/haematol.2010.029702
Pagliuca S, Michonneau D, Sicre de Fontbrune F, Sutra del Galy A, Xhaard A, Robin M, et al. Allogeneic reactivity–mediated endothelial cell complications after HSCT: a plea for consensual definitions. Blood Adv (2019) 3(15):2424–35. doi: 10.1182/bloodadvances.2019000143
Mathew NR, Vinnakota JM, Apostolova P, Erny D, Hamarsheh S, Andrieux G, et al. Graft-versus-host disease of the CNS is mediated by TNF upregulation in microglia. J Clin Invest (2020) 130(3):1315–29. doi: 10.1172/JCI130272
Belle L, Zhou V, Stuhr KL, Beatka M, Siebers EM, Knight JM, et al. Host interleukin 6 production regulates inflammation but not tryptophan metabolism in the brain during murine GVHD. JCI Insight (2017) 2(14):e93726. doi: 10.1172/jci.insight.93726
Ruggiu M, Cuccuini W, Mokhtari K, Meignin V, Peffault de Latour R, Robin M, et al. Case report: Central nervous system involvement of human graft versus host disease: Report of 7 cases and a review of literature. Medicine (2017) 96(42):e8303. doi: 10.1097/MD.0000000000008303
Flowers MED, Inamoto Y, Carpenter PA, Lee SJ, Kiem H-P, Petersdorf EW, et al. Comparative analysis of risk factors for acute graft-versus-host disease and for chronic graft-versus-host disease according to National Institutes of Health consensus criteria. Blood (2011) 117(11):3214–9. doi: 10.1182/blood-2010-08-302109
Loiseau P, Busson M, Balere M-L, Dormoy A, Bignon J-D, Gagne K, et al. HLA Association with Hematopoietic Stem Cell Transplantation Outcome: The Number of Mismatches at HLA-A, -B, -C, -DRB1, or -DQB1 Is Strongly Associated with Overall Survival. Biol Blood Marrow Transplant (2007) 13(8):965–74. doi: 10.1016/j.bbmt.2007.04.010
Saliba RM, Couriel DR, Giralt S, Rondon G, Okoroji G-J, Rashid A, et al. Prognostic value of response after upfront therapy for acute GVHD. Bone Marrow Transplant (2012) 47(1):125–31. doi: 10.1038/bmt.2011.41
Westin JR, Saliba RM, De Lima M, Alousi A, Hosing C, Qazilbash MH, et al. Steroid-Refractory Acute GVHD: Predictors and Outcomes. Adv Hematol (2011) 2011:601953. doi: 10.1155/2011/601953
Inamoto Y, Martin PJ, Storer BE, Mielcarek M, Storb RF, Carpenter PA. Response endpoints and failure-free survival after initial treatment for acute graft-versus-host disease. Haematologica (2014) 99(2):385–91. doi: 10.3324/haematol.2013.093062
Socié G, Vigouroux S, Yakoub-Agha I, Bay J-O, Fürst S, Bilger K, et al. A phase 3 randomized trial comparing inolimomab vs usual care in steroid-resistant acute GVHD. Blood (2017) 129(5):643–9. doi: 10.1182/blood-2016-09-738625
Zeiser R, von Bubnoff N, Butler J, Mohty M, Niederwieser D, Or R, et al. Ruxolitinib for Glucocorticoid-Refractory Acute Graft-versus-Host Disease. N Engl J Med (2020) 382(19):1800–10. doi: 10.1056/NEJMoa1917635
Styczyński J, Tridello G, Koster L, Iacobelli S, van Biezen A, van der Werf S, et al. Death after hematopoietic stem cell transplantation: changes over calendar year time, infections and associated factors. Bone Marrow Transplant (2020) 55(1):126–36. doi: 10.1038/s41409-019-0624-z
Zeiser R, Socié G, Blazar BR. Pathogenesis of acute graft-versus-host disease: from intestinal microbiota alterations to donor T cell activation. Br J Haematol (2016) 175(2):191–207. doi: 10.1111/bjh.14295
Zeiser R. Biology-driven developments in the therapy of acute graft-versus-host disease. Hematology (2018) 18(1):236–41. doi: 10.1182/asheducation-2018.1.236
Aversa F, Tabilio A, Velardi A, Cunningham I, Terenzi A, Falzetti F, et al. Treatment of high-risk acute leukemia with T-cell-depleted stem cells from related donors with one fully mismatched HLA haplotype. N Engl J Med (1998) 339(17):1186–93. doi: 10.1056/NEJM199810223391702
DeWolf S, Sykes M. Alloimmune T cells in transplantation. J Clin Invest (2017) 127(7):2473–81. doi: 10.1172/JCI90595
Wang Y, Singh NK, Spear TT, Hellman LM, Piepenbrink KH, McMahan RH, et al. How an alloreactive T-cell receptor achieves peptide and MHC specificity. Proc Natl Acad Sci U S A (2017) 114(24):E4792–801. doi: 10.1073/pnas.1700459114
Martin PJ, Levine DM, Storer BE, Warren EH, Zheng X, Nelson SC, et al. Genome-wide minor histocompatibility matching as related to the risk of graft-versus-host disease. Blood (2017) 129(6):791–8. doi: 10.1182/blood-2016-09-737700
Vandenhove B, Canti L, Schoemans H, Beguin Y, Baron F, Willems E, et al. Acute graft-versus-host disease: diagnosis, pathophysiology and prevention. Belg J Hematol (2020) 11(4):159–73.
Bhattacharyya ND, Feng CG. Regulation of T Helper Cell Fate by TCR Signal Strength. Front Immunol (2020) 11:624. doi: 10.3389/fimmu.2020.00624
Storb R, Deeg HJ, Whitehead J, Appelbaum F, Beatty P, Bensinger W, et al. Methotrexate and Cyclosporine Compared with Cyclosporine Alone for Prophylaxis of Acute Graft versus Host Disease after Marrow Transplantation for Leukemia. N Engl J Med (1986) 314(12):729–35. doi: 10.1056/NEJM198603203141201
Blanco B, Pérez-Simón JA, Sánchez-Abarca LI, Carvajal-Vergara X, Mateos J, Vidriales B, et al. Bortezomib induces selective depletion of alloreactive T lymphocytes and decreases the production of Th1 cytokines. Blood (2006) 107(9):3575–83. doi: 10.1182/blood-2005-05-2118
Pai C-CS, Hsiao H-H, Sun K, Chen M, Hagino T, Tellez J, et al. Therapeutic benefit of bortezomib on acute graft-versus-host disease is tissue specific and is associated with interleukin-6 levels. Biol Blood Marrow Transplant (2014) 20(12):1899–904. doi: 10.1016/j.bbmt.2014.07.022
Vodanovic-Jankovic S, Hari P, Jacobs P, Komorowski R, Drobyski WR. NF-kappaB as a target for the prevention of graft-versus-host disease: comparative efficacy of bortezomib and PS-1145. Blood (2006) 107(2):827–34. doi: 10.1182/blood-2005-05-1820
Kumar S, Leigh ND, Cao X. The Role of Co-stimulatory/Co-inhibitory Signals in Graft-vs.-Host Disease. Front Immunol (2018) 9:3003. doi: 10.3389/fimmu.2018.03003
Hill GR, Koyama M. Cytokines and Co-stimulation in Acute Graft-versus-Host Disease. Blood (2020) 136(4):418–28. doi: 10.11182/blood.2019000952
Wallace PM, Johnson JS, MacMaster JF, Kennedy KA, Gladstone P, Linsley PS. CTLA4Ig treatment ameliorates the lethality of murine graft-versus-host disease across major histocompatibility complex barriers. Transplantation (1994) 58(5):602–10. doi: 10.1097/00007890-199409150-00013
Watkins BK, Tkachev V, Furlan SN, Hunt DJ, Betz K, Yu A, et al. CD28 blockade controls T cell activation to prevent graft-versus-host disease in primates. J Clin Invest (2018) 128(9):3991–4007. doi: 10.1172/JCI98793
Blazar BR, Taylor PA, Linsley PS, Vallera DA. In vivo blockade of CD28/CTLA4: B7/BB1 interaction with CTLA4-Ig reduces lethal murine graft-versus-host disease across the major histocompatibility complex barrier in mice. Blood (1994) 83(12):3815–25. doi: 10.1182/blood.V83.12.3815.bloodjournal83123815
Blazar BR, Sharpe AH, Taylor PA, Panoskaltsis-Mortari A, Gray GS, Korngold R, et al. Infusion of anti-B7.1 (CD80) and anti-B7.2 (CD86) monoclonal antibodies inhibits murine graft-versus-host disease lethality in part via direct effects on CD4+ and CD8+ T cells. J Immunol (1996) 157(8):3250–9.
Kim S, Reddy P. Targeting Signal 3 Extracellularly and Intracellularly in Graft-Versus-Host Disease. Front Immunol (2020) 11:722. doi: 10.3389/fimmu.2020.00722
Myers DR, Wheeler B, Roose JP. mTOR and other effector kinase signals that impact T cell function and activity. Immunol Rev (2019) 291(1):134–53. doi: 10.1111/imr.12796
Mannina D, Kröger N. Janus Kinase Inhibition for Graft-Versus-Host Disease: Current Status and Future Prospects. Drugs (2019) 79(14):1499–509. doi: 10.1007/s40265-019-01174-1
Elli EM, Baratè C, Mendicino F, Palandri F, Palumbo GA. Mechanisms Underlying the Anti-inflammatory and Immunosuppressive Activity of Ruxolitinib. Front Oncol (2019) 9:1186. doi: 10.3389/fonc.2019.01186
Delens L, Ehx G, Somja J, Vrancken L, Belle L, Seidel L, et al. In Vitro Th17-Polarized Human CD4+ T Cells Exacerbate Xenogeneic Graft-versus-Host Disease. Biol Blood Marrow Transplant (2019) 25(2):204–15. doi: 10.1016/j.bbmt.2018.10.007
Drobyski WR, Szabo A, Zhu F, Keever-Taylor C, Hebert KM, Dunn R, et al. Tocilizumab, tacrolimus and methotrexate for the prevention of acute graft-versus-host disease: low incidence of lower gastrointestinal tract disease. Haematologica (2018) 103(4):717–27. doi: 10.3324/haematol.2017.183434
Kennedy GA, Varelias A, Vuckovic S, Le Texier L, Gartlan KH, Zhang P, 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):1451–9. doi: 10.1016/S1470-2045(14)71017-4
Kang S, Tanaka T, Narazaki M, Kishimoto T. Targeting Interleukin-6 Signaling in Clinic. Immunity (2019) 50(4):1007–23. doi: 10.1016/j.immuni.2019.03.026
Wilkinson AN, Chang K, Kuns RD, Henden AS, Minnie SA, Ensbey KS, et al. IL-6 dysregulation originates in dendritic cells and mediates graft-versus-host disease via classical signaling. Blood (2019) 134(23):2092–106. doi: 10.1182/blood.2019000396
Blazar BR, Taylor PA, Panoskaltsis-Mortari A, Vallera DA. Rapamycin inhibits the generation of graft-versus-host disease- and graft-versus-leukemia-causing T cells by interfering with the production of Th1 or Th1 cytotoxic cytokines. J Immunol (1998) 160(11):5355–65.
Zeiser R, Leveson-Gower DB, Zambricki EA, Kambham N, Beilhack A, Loh J, et al. Differential impact of mammalian target of rapamycin inhibition on CD4+CD25+Foxp3+ regulatory T cells compared with conventional CD4+ T cells. Blood (2008) 111(1):453–62. doi: 10.1182/blood-2007-06-094482
Tijaro-Ovalle NM, Karantanos T, Wang H-T, Boussiotis VA. Metabolic Targets for Improvement of Allogeneic Hematopoietic Stem Cell Transplantation and Graft-vs.-Host Disease. Front Immunol (2019) 10:295. doi: 10.3389/fimmu.2019.00295
Nguyen HD, Chatterjee S, Haarberg KMK, Wu Y, Bastian D, Heinrichs J, et al. Metabolic reprogramming of alloantigen-activated T cells after hematopoietic cell transplantation. J Clin Invest (2016) 126(4):1337–52. doi: 10.1172/JCI82587
Koyama M, Mukhopadhyay P, Schuster IS, Henden AS, Hülsdünker J, Varelias A, et al. MHC Class II Antigen Presentation by the Intestinal Epithelium Initiates Graft-versus-Host Disease and Is Influenced by the Microbiota. Immunity (2019) 51(5):885–98.e7. doi: 10.1016/j.immuni.2019.08.011
Koyama M, Kuns RD, Olver SD, Raffelt NC, Wilson YA, Don ALJ, et al. Recipient nonhematopoietic antigen-presenting cells are sufficient to induce lethal acute graft-versus-host disease. Nat Med (2011) 18(1):135–42. doi: 10.1038/nm.2597
Toubai T, Mathewson ND, Magenau J, Reddy P. Danger Signals and Graft-versus-host Disease: Current Understanding and Future Perspectives. Front Immunol (2016) 7:539. doi: 10.3389/fimmu.2016.00539
Jones JM, Wilson R, Bealmear PM. Mortality and gross pathology of secondary disease in germfree mouse radiation chimeras. Radiat Res (1971) 45(3):577–88. doi: 10.2307/3573066
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):401–4. doi: 10.1093/jnci/52.2.401
van Bekkum DW, Knaan S. Role of bacterial microflora in development of intestinal lesions from graft-versus-host reaction. J Natl Cancer Inst (1977) 58(3):787–90. doi: 10.1093/jnci/58.3.787
Fredricks DN. The gut microbiota and graft-versus-host disease. J Clin Invest (2019) 129(5):1808–17. doi: 10.1172/JCI125797
Socié G, Mary J-Y, Lemann M, Daneshpouy M, Guardiola P, Meignin V, et al. Prognostic value of apoptotic cells and infiltrating neutrophils in graft-versus-host disease of the gastrointestinal tract in humans: TNF and Fas expression. Blood (2004) 103(1):50–7. doi: 10.1182/blood-2003-03-0909
Schwab L, Goroncy L, Palaniyandi S, Gautam S, Triantafyllopoulou A, Mocsai A, et al. Neutrophil granulocytes recruited upon translocation of intestinal bacteria enhance graft-versus-host disease via tissue damage. Nat Med (2014) 20(6):648–54. doi: 10.1038/nm.3517
Kittan NA, Hildebrandt GC. The Chemokine System: A Possible Therapeutic Target in Acute Graft Versus Host Disease. Curr Top Microbiol Immunol (2010) 341:97–120. doi: 10.1007/82_2010_23
Zheng H, Matte-Martone C, Li H, Anderson BE, Venketesan S, Sheng Tan H, et al. Effector memory CD4+ T cells mediate graft-versus-leukemia without inducing graft-versus-host disease. Blood (2008) 111(4):2476–84. doi: 10.1182/blood-2007-08-109678
Chen BJ, Deoliveira D, Cui X, Le NT, Son J, Whitesides JF, et al. Inability of memory T cells to induce graft-versus-host disease is a result of an abortive alloresponse. Blood (2007) 109(7):3115–23. doi: 10.1182/blood-2006-04-016410
Yuan J, Ren H, Shi Y, Liu W. Prophylaxis of acute graft-versus-host disease by CCR5 blockade combined with cyclosporine A in a murine model. Inflammation Res (2015) 64(2):137–44. doi: 10.1007/s00011-014-0793-6
Reshef R, Luger SM, Hexner EO, Loren AW, Frey NV, Nasta SD, et al. Blockade of lymphocyte chemotaxis in visceral graft-versus-host disease. N Engl J Med (2012) 367(2):135–45. doi: 10.1056/NEJMoa1201248
Dutt S, Ermann J, Tseng D, Liu YP, George TI, Fathman CG, et al. L-selectin and beta7 integrin on donor CD4 T cells are required for the early migration to host mesenteric lymph nodes and acute colitis of graft-versus-host disease. Blood (2005) 106(12):4009–15. doi: 10.1182/blood-2005-06-2339
Petrovic A, Alpdogan O, Willis LM, Eng JM, Greenberg AS, Kappel BJ, et al. LPAM (alpha 4 beta 7 integrin) is an important homing integrin on alloreactive T cells in the development of intestinal graft-versus-host disease. Blood (2004) 103(4):1542–7. doi: 10.1182/blood-2003-03-0957
Caridade M, Graca L, Ribeiro RM. Mechanisms Underlying CD4+ Treg Immune Regulation in the Adult: From Experiments to Models. Front Immunol (2013) 4:378. doi: 10.3389/fimmu.2013.00378
Liston A, Gray DHD. Homeostatic control of regulatory T cell diversity. Nat Rev Immunol (2014) 14(3):154–65. doi: 10.1038/nri3605
Schiavon V, Duchez S, Branchtein M, How-Kit A, Cassius C, Daunay A, et al. Microenvironment tailors nTreg structure and function. Proc Natl Acad Sci U S A (2019) 116(13):6298–307. doi: 10.1073/pnas.1812471116
Chinen T, Kannan AK, Levine AG, Fan X, Klein U, Zheng Y, et al. An essential role for the IL-2 receptor in T(reg) cell function. Nat Immunol (2016) 17(11):1322–33. doi: 10.1038/ni.3540
Cohen JL, Trenado A, Vasey D, Klatzmann D, Salomon BL. CD4(+)CD25(+) immunoregulatory T Cells: new therapeutics for graft-versus-host disease. J Exp Med (2002) 196(3):401–6. doi: 10.1084/jem.20020090
Hannon M, Lechanteur C, Lucas S, Somja J, Seidel L, Belle L, et al. Infusion of clinical-grade enriched regulatory T cells delays experimental xenogeneic graft-versus-host disease. Transfusion (2014) 54(2):353–63. doi: 10.1111/trf.12279
Zhou X, Bailey-Bucktrout SL, Jeker LT, Penaranda C, Martínez-Llordella M, Ashby M, et al. Instability of the transcription factor Foxp3 leads to the generation of pathogenic memory T cells in vivo. Nat Immunol (2009) 10(9):1000–7. doi: 10.1038/ni.1774
Rubtsov YP, Niec RE, Josefowicz S, Li L, Darce J, Mathis D, et al. Stability of the regulatory T cell lineage in vivo. Science (2010) 329(5999):1667–71. doi: 10.1126/science.1191996
Lu L, Lan Q, Li Z, Zhou X, Gu J, Li Q, et al. Critical role of all-trans retinoic acid in stabilizing human natural regulatory T cells under inflammatory conditions. Proc Natl Acad Sci U S A (2014) 111(33):E3432–40. doi: 10.1073/pnas.1408780111
Fu W, Ergun A, Lu T, Hill JA, Haxhinasto S, Fassett MS, et al. A multiply redundant genetic switch “locks in” the transcriptional signature of regulatory T cells. Nat Immunol (2012) 13(10):972–80. doi: 10.1038/ni.2420
Ehx G, Fransolet G, de Leval L, D’Hondt S, Lucas S, Hannon M, et al. Azacytidine prevents experimental xenogeneic graft-versus-host disease without abrogating graft-versus-leukemia effects. Oncoimmunology (2017) 6(5):e1314425. doi: 10.1080/2162402X.2017.1314425
Gregori S, Roncarolo MG. Engineered T Regulatory Type 1 Cells for Clinical Application. Front Immunol (2018) 9:233. doi: 10.3389/fimmu.2018.00233
Locafaro G, Andolfi G, Russo F, Cesana L, Spinelli A, Camisa B, et al. IL-10-Engineered Human CD4(+) Tr1 Cells Eliminate Myeloid Leukemia in an HLA Class I-Dependent Mechanism. Mol Ther (2017) 25(10):2254–69. doi: 10.1016/j.ymthe.2017.06.029
Blazar BR, MacDonald KPA, Hill GR. Immune regulatory cell infusion for graft-versus-host disease prevention and therapy. Blood (2018) 131(24):2651–60. doi: 10.1182/blood-2017-11-785865
Negrin RS. Immune regulation in hematopoietic cell transplantation. Bone Marrow Transplant (2019) 54(S2):765–8. doi: 10.1038/s41409-019-0600-7
Wang Z, Liu X, Cao F, Bellanti JA, Zhou J, Zheng SG. Prospects of the Use of Cell Therapy to Induce Immune Tolerance. Front Immunol (2020) 11:792. doi: 10.3389/fimmu.2020.00792
Coman T, Rossignol J, D’Aveni M, Fabiani B, Dussiot M, Rignault R, et al. Human CD4- invariant NKT lymphocytes regulate graft versus host disease. Oncoimmunology (2018) 7(11):e1470735. doi: 10.1080/2162402X.2018.1470735
Schneidawind D, Pierini A, Alvarez M, Pan Y, Baker J, Buechele C, et al. CD4+ invariant natural killer T cells protect from murine GVHD lethality through expansion of donor CD4+CD25+FoxP3+ regulatory T cells. Blood (2014) 124(22):3320–8. doi: 10.1182/blood-2014-05-576017
Wu S-R, Reddy P. Tissue tolerance: a distinct concept to control acute GVHD severity. Blood (2017) 129(13):1747–52. doi: 10.1182/blood-2016-09-740431
Wu S-R, Reddy P. Regulating Damage from Sterile Inflammation: A Tale of Two Tolerances. Trends Immunol (2017) 38(4):231–5. doi: 10.1016/j.it.2017.02.005
Hayase E, Hashimoto D, Nakamura K, Noizat C, Ogasawara R, Takahashi S, et al. R-Spondin1 expands Paneth cells and prevents dysbiosis induced by graft-versus-host disease. J Exp Med (2017) 214(12):3507–18. doi: 10.1084/jem.20170418
Norona J, Apostolova P, Schmidt D, Ihlemann R, Reischmann N, Taylor G, et al. Glucagon like peptide-2 for Intestinal stem cell and Paneth cell repair during graft-versus-host disease in mice and humans. Blood (2020) 136(12):1442–45. doi: 10.1182/blood.2020005957
Vanclée A, Lutgens LCHW, Oving EBH, Deutz NEP, Gijbels MJJ, Schouten HC, et al. Keratinocyte growth factor ameliorates acute graft-versus-host disease in a novel nonmyeloablative haploidentical transplantation model. Bone Marrow Transplant (2005) 36(10):907–15. doi: 10.1038/sj.bmt.1705157
Hanash AM, Dudakov JA, Hua G, O’Connor MH, Young LF, Singer NV, 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):339–50. doi: 10.1016/j.immuni.2012.05.028
Dudakov JA, Hanash AM, van den Brink MRM. Interleukin-22: Immunobiology and Pathology. Annu Rev Immunol (2015) 33(1):747–85. doi: 10.1146/annurev-immunol-032414-112123
Köhler N, Zeiser R. Intestinal Microbiota Influence Immune Tolerance Post Allogeneic Hematopoietic Cell Transplantation and Intestinal GVHD. Front Immunol (2018) 9:3179. doi: 10.3389/fimmu.2018.03179
Peled JU, Gomes ALC, Devlin SM, Littmann ER, Taur Y, Sung AD, et al. Microbiota as Predictor of Mortality in Allogeneic Hematopoietic-Cell Transplantation. N Engl J Med (2020) 382(9):822–34. doi: 10.1056/NEJMoa1900623
Holler E, Butzhammer P, Schmid K, Hundsrucker C, Koestler J, Peter 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):640–5. doi: 10.1016/j.bbmt.2014.01.030
Payen M, Nicolis I, Robin M, Michonneau D, Delannoye J, Mayeur C, et al. Functional and phylogenetic alterations in gut microbiome are linked to graft-versus-host disease severity. Blood Adv (2020) 4(9):1824–32. doi: 10.1182/bloodadvances.2020001531
Taur Y, Jenq RR, Perales M-A, Littmann ER, Morjaria S, Ling L, et al. The effects of intestinal tract bacterial diversity on mortality following allogeneic hematopoietic stem cell transplantation. Blood (2014) 124(7):1174–82. doi: 10.1182/blood-2014-02-554725
Legoff J, Resche-Rigon M, Bouquet J, Robin M, Naccache SN, Mercier-Delarue S, et al. The eukaryotic gut virome in hematopoietic stem cell transplantation: new clues in enteric graft-versus-host disease. Nat Med (2017) 23(9):1080–5. doi: 10.1038/nm.4380
Jenq RR, Taur Y, Devlin SM, Ponce DM, Goldberg JD, Ahr KF, et al. Intestinal Blautia Is Associated with Reduced Death from Graft-versus-Host Disease. Biol Blood Marrow Transplant (2015) 21(8):1373–83. doi: 10.1016/j.bbmt.2015.04.016
Nishi K, Kanda J, Hishizawa M, Kitano T, Kondo T, Yamashita K, et al. Impact of the Use and Type of Antibiotics on Acute Graft-versus-Host Disease. Biol Blood Marrow Transplant J Am Soc Blood Marrow Transplant (2018) 24(11):2178–83. doi: 10.1016/j.bbmt.2018.06.031
Shono Y, Docampo MD, Peled JU, Perobelli SM, Velardi E, Tsai JJ, 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. doi: 10.1126/scitranslmed.aaf2311
Simms-Waldrip TR, Sunkersett G, Coughlin LA, Savani MR, Arana C, Kim J, et al. Antibiotic-Induced Depletion of Anti-inflammatory Clostridia Is Associated with the Development of Graft-versus-Host Disease in Pediatric Stem Cell Transplantation Patients. Biol Blood Marrow Transplant (2017) 23(5):820–9. doi: 10.1016/j.bbmt.2017.02.004
Riwes M, Reddy P. Short chain fatty acids: Postbiotics/metabolites and graft versus host disease colitis. Semin Hematol (2020) 57(1):1–6. doi: 10.1053/j.seminhematol.2020.06.001
Riwes M, Reddy P. Microbial metabolites and graft versus host disease. Am J Transplant Off J Am Soc Transplant Am Soc Transpl Surg (2018) 18(1):23–9. doi: 10.1111/ajt.14443
Michonneau D, Latis E, Curis E, Dubouchet L, Ramamoorthy S, Ingram B, et al. Metabolomics analysis of human acute graft-versus-host disease reveals changes in host and microbiota-derived metabolites. Nat Commun (2019) 10(1):5695. doi: 10.1038/s41467-019-13498-3
Mathewson ND, Jenq R, Mathew AV, Koenigsknecht M, Hanash A, Toubai T, et al. Gut microbiome-derived metabolites modulate intestinal epithelial cell damage and mitigate graft-versus-host disease. Nat Immunol (2016) 17(5):505–13. doi: 10.1038/ni.3400
Servais S, Beguin Y, Delens L, Ehx G, Fransolet G, Hannon M, et al. Novel approaches for preventing acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Expert Opin Invest Drugs (2016) 25(8):957–72. doi: 10.1080/13543784.2016.1182498
Penack O, Marchetti M, Ruutu T, Aljurf M, Bacigalupo A, Bonifazi F, et al. Prophylaxis and management of graft versus host disease after stem-cell transplantation for haematological malignancies: updated consensus recommendations of the European Society for Blood and Marrow Transplantation. Lancet Haematol (2020) 7(2):e157–67. doi: 10.1016/S2352-3026(19)30256-X
Zeiser R, Negrin RS. Interleukin-2 receptor downstream events in regulatory T cells: Implications for the choice of immunosuppressive drug therapy. Cell Cycle (2008) 7(4):458–62. doi: 10.4161/cc.7.4.5454
Cutler C, Logan B, Nakamura R, Johnston L, Choi S, Porter D, et al. Tacrolimus/sirolimus vs tacrolimus/methotrexate as GVHD prophylaxis after matched, related donor allogeneic HCT. Blood (2014) 124(8):1372–7. doi: 10.1182/blood-2014-04-567164
Sandmaier BM, Kornblit B, Storer BE, Olesen G, Maris MB, Langston AA, et al. Addition of sirolimus to standard cyclosporine plus mycophenolate mofetil-based graft-versus-host disease prophylaxis for patients after unrelated non-myeloablative haemopoietic stem cell transplantation: a multicentre, randomised, phase 3 trial. Lancet Haematol (2019) 6(8):e409–18. doi: 10.1016/S2352-3026(19)30088-2
Cutler C, Stevenson K, Kim HT, Richardson P, Ho VT, Linden E, et al. Sirolimus is associated with veno-occlusive disease of the liver after myeloablative allogeneic stem cell transplantation. Blood (2008) 112(12):4425–31. doi: 10.1182/blood-2008-07-169342
Walker I, Panzarella T, Couban S, Couture F, Devins G, Elemary M, et al. Pretreatment with anti-thymocyte globulin versus no anti-thymocyte globulin in patients with haematological malignancies undergoing haemopoietic cell transplantation from unrelated donors: a randomised, controlled, open-label, phase 3, multicentre trial. Lancet Oncol (2016) 17(2):164–73. doi: 10.1016/S1470-2045(15)00462-3
Socie G, Schmoor C, Bethge WA, Ottinger HD, Stelljes M, Zander AR, et al. Chronic graft-versus-host disease: long-term results from a randomized trial on graft-versus-host disease prophylaxis with or without anti-T-cell globulin ATG-Fresenius. Blood (2011) 117(23):6375–82. doi: 10.1182/blood-2011-01-329821
Kröger N, Solano C, Wolschke C, Bandini G, Patriarca F, Pini M, et al. Antilymphocyte Globulin for Prevention of Chronic Graft-versus-Host Disease. N Engl J Med (2016) 374(1):43–53. doi: 10.1056/NEJMoa1506002
Soiffer RJ, Kim HT, McGuirk J, Horwitz ME, Johnston L, Patnaik MM, et al. Prospective, Randomized, Double-Blind, Phase III Clinical Trial of Anti-T-Lymphocyte Globulin to Assess Impact on Chronic Graft-Versus-Host Disease-Free Survival in Patients Undergoing HLA-Matched Unrelated Myeloablative Hematopoietic Cell Transplantatio. J Clin Oncol (2017) 35(36):4003–11. doi: 10.1200/JCO.2017.75.8177
Bonifazi F, Solano C, Wolschke C, Sessa M, Patriarca F, Zallio F, et al. Acute GVHD prophylaxis plus ATLG after myeloablative allogeneic haemopoietic peripheral blood stem-cell transplantation from HLA-identical siblings in patients with acute myeloid leukaemia in remission: final results of quality of life and long-term outcome analysis of a phase 3 randomised study. Lancet Haematol (2019) 6(2):e89–99. doi: 10.1016/S2352-3026(18)30214-X
Soiffer RJ, Lerademacher J, Ho V, Kan F, Artz A, Champlin RE, et al. Impact of immune modulation with anti-T-cell antibodies on the outcome of reduced-intensity allogeneic hematopoietic stem cell transplantation for hematologic malignancies. Blood (2011) 117(25):6963–70. doi: 10.1182/blood-2011-01-332007
Servais S, Menten-Dedoyart C, Beguin Y, Seidel L, Gothot A, Daulne C, et al. Impact of Pre-Transplant Anti-T Cell Globulin (ATG) on Immune Recovery after Myeloablative Allogeneic Peripheral Blood Stem Cell Transplantation. Boussiotis VA, editor. PLoS One (2015) 10(6):e0130026. doi: 10.1371/journal.pone.0130026
Hannon M, Beguin Y, Ehx G, Servais S, Seidel L, Graux C, et al. Immune Recovery after Allogeneic Hematopoietic Stem Cell Transplantation Following Flu-TBI versus TLI-ATG Conditioning. Clin Cancer Res (2015) 21(14):3131–9. doi: 10.1158/1078-0432.CCR-14-3374
Ali R, Ramdial J, Algaze S, Beitinjaneh A. The Role of Anti-Thymocyte Globulin or Alemtuzumab-Based Serotherapy in the Prophylaxis and Management of Graft-Versus-Host Disease. Biomedicines (2017) 5(4):67. doi: 10.3390/biomedicines5040067
Baron F, Mohty M, Blaise D, Socié G, Labopin M, Esteve J, et al. Anti-thymocyte globulin as graft-versus-host disease prevention in the setting of allogeneic peripheral blood stem cell transplantation: a review from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation. Haematologica (2017) 102(2):224–34. doi: 10.3324/haematol.2016.148510
von dem Borne PA, Starrenburg CWJI, Halkes SJM, Marijt WAE, Fibbe WE, Falkenburg JHF, et al. Reduced-intensity conditioning allogeneic stem cell transplantation with donor T-cell depletion using alemtuzumab added to the graft (‘Campath in the bag’). Curr Opin Oncol (2009) 21(1):S27–9. doi: 10.1097/01.cco.0000357472.76337.0e
Pasquini MC, Devine S, Mendizabal A, Baden LR, Wingard JR, Lazarus HM, et al. Comparative outcomes of donor graft CD34+ selection and immune suppressive therapy as graft-versus-host disease prophylaxis for patients with acute myeloid leukemia in complete remission undergoing HLA-matched sibling allogeneic hematopoietic cell transplantation. J Clin Oncol (2012) 30(26):3194–201. doi: 10.1200/JCO.2012.41.7071
Ho VT. The history and future of T-cell depletion as graft-versus-host disease prophylaxis for allogeneic hematopoietic stem cell transplantation. Blood (2001) 98(12):3192–204. doi: 10.1182/blood.V98.12.3192
Nunes NS, Kanakry CG. Mechanisms of Graft-versus-Host Disease Prevention by Post-transplantation Cyclophosphamide: An Evolving Understanding. Front Immunol (2019) 10:2668. doi: 10.3389/fimmu.2019.02668
Luznik L, Bolanos-Meade J, Zahurak M, Chen AR, Smith BD, Brodsky R, et al. High-dose cyclophosphamide as single-agent, short-course prophylaxis of graft-versus-host disease. Blood (2010) 115(16):3224–30. doi: 10.1182/blood-2009-11-251595
Luznik L, O’Donnell PV, Fuchs EJ. Post-transplantation cyclophosphamide for tolerance induction in HLA-haploidentical bone marrow transplantation. Semin Oncol (2012) 39(6):683–93. doi: 10.1053/j.seminoncol.2012.09.005
Luznik L, O’Donnell PV, Symons HJ, Chen AR, Leffell MS, Zahurak M, et al. HLA-haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide. Biol Blood Marrow Transplant (2008) 14(6):641–50. doi: 10.1016/j.bbmt.2008.03.005
Eto M, Mayumi H, Tomita Y, Yoshikai Y, Nishimura Y, Nomoto K. The requirement of intrathymic mixed chimerism and clonal deletion for a long-lasting skin allograft tolerance in cyclophosphamide-induced tolerance. Eur J Immunol (1990) 20(9):2005–13. doi: 10.1002/eji.1830200919
Eto M, Mayumi H, Tomita Y, Yoshikai Y, Nishimura Y, Nomoto K. Sequential mechanisms of cyclophosphamide-induced skin allograft tolerance including the intrathymic clonal deletion followed by late breakdown of the clonal deletion. J Immunol (1990) 145(5):1303–10.
Kanakry CG, Ganguly S, Zahurak M, Bolaños-Meade J, Thoburn C, Perkins B, et al. Aldehyde dehydrogenase expression drives human regulatory T cell resistance to posttransplantation cyclophosphamide. Sci Transl Med (2013) 5(211):211ra157. doi: 10.1126/scitranslmed.3006960
Ganguly S, Ross DB, Panoskaltsis-Mortari A, Kanakry CG, Blazar BR, Levy RB, et al. Donor CD4+ Foxp3+ regulatory T cells are necessary for posttransplantation cyclophosphamide-mediated protection against GVHD in mice. Blood (2014) 124(13):2131–41. doi: 10.1182/blood-2013-10-525873
Baumeister SHC, Rambaldi B, Shapiro RM, Romee R. Key Aspects of the Immunobiology of Haploidentical Hematopoietic Cell Transplantation. Front Immunol (2020) 11:191. doi: 10.3389/fimmu.2020.00191
El Fakih R, Hashmi SK, Ciurea SO, Luznik L, Gale RP, Aljurf M. Post-transplant cyclophosphamide use in matched HLA donors: a review of literature and future application. Bone Marrow Transplant (2019) 55(1):40–7. doi: 10.1038/s41409-019-0547-8
Bolaños-Meade J, Reshef R, Fraser R, Fei M, Abhyankar S, Al-Kadhimi Z, et al. Three prophylaxis regimens (tacrolimus, mycophenolate mofetil, and cyclophosphamide; tacrolimus, methotrexate, and bortezomib; or tacrolimus, methotrexate, and maraviroc) versus tacrolimus and methotrexate for prevention of graft-versus-host disease with haemopoietic cell transplantation with reduced-intensity conditioning: a randomised phase 2 trial with a non-randomised contemporaneous control group (BMT CTN 1203). Lancet Haematol (2019) 6(3):e132–43. doi: 10.1016/S2352-3026(18)30221-7
Jacoby E, Varda-Bloom N, Goldstein G, Hutt D, Churi C, Vernitsky H, et al. Comparison of two cytoreductive regimens for αβ-T-cell-depleted haploidentical HSCT in pediatric malignancies: Improved engraftment and outcome with TBI-based regimen. Pediatr Blood Cancer (2018) 65(2):e26839. doi: 10.1002/pbc.26839
Bleakley M, Heimfeld S, Loeb KR, Jones LA, Chaney C, Seropian S, et al. Outcomes of acute leukemia patients transplanted with naive T cell-depleted stem cell grafts. J Clin Invest (2015) 125(7):2677–89. doi: 10.1172/JCI81229
Roy DC, Lachance S, Cohen S, Delisle J, Kiss T, Sauvageau G, et al. Allodepleted T-cell immunotherapy after haploidentical haematopoietic stem cell transplantation without severe acute graft-versus-host disease (GVHD) in the absence of GVHD prophylaxis. Br J Haematol (2019) 186(5):754–66. doi: 10.1111/bjh.15970
Koreth J, Kim HT, Lange PB, Bindra B, Reynolds CG, Chammas MJ, et al. A Bortezomib-Based Regimen Offers Promising Survival and Graft-versus-Host Disease Prophylaxis in Myeloablative HLA-Mismatched and Unrelated Donor Transplantation: A Phase II Trial. Biol Blood Marrow Transplant (2015) 21(11):1907–13. doi: 10.1016/j.bbmt.2015.05.027
Koreth J, Kim HT, Lange PB, Poryanda SJ, Reynolds CG, Rai SC, et al. Bortezomib-based immunosuppression after reduced-intensity conditioning hematopoietic stem cell transplantation: randomized phase II results. Haematologica (2018) 103(3):522–30. doi: 10.3324/haematol.2017.176859
Khandelwal P, Yeh RF, Yu L, Lane A, Dandoy CE, El-Bietar J, et al. Graft Versus Host Disease Prophylaxis With Abatacept Reduces Severe Acute Graft Versus Host Disease in Allogeneic Hematopoietic Stem Cell Transplant for Beta Thalassemia Major with Busulfan, Fludarabine, and Thiotepa. Transplantation (2020). doi: 10.1097/TP.0000000000003327. online ehaed of print.
Koura DT, Horan JT, Langston AA, Qayed M, Mehta A, Khoury HJ, et al. In vivo T cell costimulation blockade with abatacept for acute graft-versus-host disease prevention: a first-in-disease trial. Biol Blood Marrow Transplant (2013) 9(11):1638–49. doi: 10.1016/j.bbmt.2013.09.003
Jaiswal SR, Bhakuni P, Aiyer HM, Soni M, Bansal S, Chakrabarti S. CTLA4Ig in an Extended Schedule along with Sirolimus Improves Outcome with a Distinct Pattern of Immune Reconstitution Following Post-Transplantation Cyclophosphamide-Based Haploidentical Transplantation for Hemoglobinopathies. Biol Blood Marrow Transplant (2020) 26(8):1469–76. doi: 10.1016/j.bbmt.2020.05.005
Jaiswal SR, Bhakuni P, Zaman S, Bansal S, Bharadwaj P, Bhargava S, et al. T cell costimulation blockade promotes transplantation tolerance in combination with sirolimus and post-transplantation cyclophosphamide for haploidentical transplantation in children with severe aplastic anemia. Transpl Immunol (2017) 43–44:54–9. doi: 10.1016/j.trim.2017.07.004
Jaiswal SR, Bhakuni P, Joy A, Kaushal S, Chakrabarti A, Chakrabarti S. CTLA4Ig Primed Donor Lymphocyte Infusion: A Novel Approach to Immunotherapy after Haploidentical Transplantation for Advanced Leukemia. Biol Blood Marrow Transplant (2019) 25(4):673–82. doi: 10.1016/j.bbmt.2018.12.836
Goodyear OC, Dennis M, Jilani NY, Loke J, Siddique S, Ryan G, et al. Azacitidine augments expansion of regulatory T cells after allogeneic stem cell transplantation in patients with acute myeloid leukemia (AML). Blood (2012) 119(14):3361–9. doi: 10.1182/blood-2011-09-377044
Choi SW, Braun T, Henig I, Gatza E, Magenau J, Parkin B, et al. Vorinostat plus tacrolimus/methotrexate to prevent GVHD after myeloablative conditioning, unrelated donor HCT. Blood (2017) 130(15):1760–7. doi: 10.1182/blood-2017-06-790469
Choi SW, Braun T, Chang L, Ferrara JLM, Pawarode A, Magenau JM, et al. Vorinostat plus tacrolimus and mycophenolate to prevent graft-versus-host disease after related-donor reduced-intensity conditioning allogeneic haemopoietic stem-cell transplantation: a phase 1/2 trial. Lancet Oncol (2014) 15(1):87–95. doi: 10.1016/S1470-2045(13)70512-6
Khandelwal P, Fukuda T, Teusink-Cross A, Kashuba ADM, Lane A, Mehta PA, et al. CCR5 inhibitor as novel acute graft versus host disease prophylaxis in children and young adults undergoing allogeneic stem cell transplant: results of the phase II study. Bone Marrow Transplant (2020) 55(8):1552–9. doi: 10.1038/s41409-020-0888-3
Chen Y-B, Shah NN, Renteria AS, Cutler C, Jansson J, Akbari M, et al. Vedolizumab for prevention of graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Blood Adv (2019) 3(23):4136–46. doi: 10.1182/bloodadvances.2019000893
Kennedy-Nasser AA, Ku S, Castillo-Caro P, Hazrat Y, Wu M-F, Liu H, et al. Ultra low-dose IL-2 for GVHD prophylaxis after allogeneic hematopoietic stem cell transplantation mediates expansion of regulatory T cells without diminishing antiviral and antileukemic activity. Clin Cancer Res (2014) 20(8):2215–25. doi: 10.1158/1078-0432.CCR-13-3205
Betts BC, Pidala J, Kim J, Mishra A, Nishihori T, Perez L, et al. IL-2 promotes early Treg reconstitution after allogeneic hematopoietic cell transplantation. Haematologica (2017) 102(5):948–57. doi: 10.3324/haematol.2016.153072
Elias S, Rudensky AY. Therapeutic use of regulatory T cells for graft-versus-host disease. Br J Haematol (2019) 187(1):25–38. doi: 10.1111/bjh.16157
Zhao L, Chen S, Yang P, Cao H, Li L. The role of mesenchymal stem cells in hematopoietic stem cell transplantation: prevention and treatment of graft-versus-host disease. Stem Cell Res Ther (2019) 10(1):182. doi: 10.1186/s13287-019-1287-9
Chen Y-B, Efebera YA, Johnston L, Ball ED, Avigan D, Lekakis LJ, et al. Increased Foxp3(+)Helios(+) Regulatory T Cells and Decreased Acute Graft-versus-Host Disease after Allogeneic Bone Marrow Transplantation in Patients Receiving Sirolimus and RGI-2001, an Activator of Invariant Natural Killer T Cells. Biol Blood Marrow Transplant (2017) 23(4):625–34. doi: 10.1016/j.bbmt.2017.01.069
Yeh AC, Brunner AM, Spitzer TR, Chen Y-B, Coughlin E, McAfee S, et al. Phase I Study of Urate Oxidase in the Reduction of Acute Graft-Versus-Host Disease after Myeloablative Allogeneic Stem Cell Transplantation. Biol Blood Marrow Transplant (2014) 20(5):730–4. doi: 10.1016/j.bbmt.2014.02.003
Jagasia MH, Abonour R, Long GD, Bolwell BJ, Laport GG, Shore TB, et al. Palifermin for the reduction of acute GVHD: a randomized, double-blind, placebo-controlled trial. Bone Marrow Transplant (2012) 47(10):1350–5. doi: 10.1038/bmt.2011.261
Blazar BR, Weisdorf DJ, Defor T, Goldman A, Braun T, Silver S, et al. Phase 1/2 randomized, placebo-control trial of palifermin to prevent graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (HSCT). Blood (2006) 108(9):3216–22. doi: 10.1182/blood-2006-04-017780
DeFilipp Z, Hohmann E, Jenq RR, Chen Y-B. Fecal Microbiota Transplantation: Restoring the Injured Microbiome after Allogeneic Hematopoietic Cell Transplantation. Biol Blood Marrow Transplant (2019) 25(1):e17–22. doi: 10.1016/j.bbmt.2018.10.022
DeFilipp Z, Peled JU, Li S, Mahabamunuge J, Dagher Z, Slingerland AE, et al. Third-party fecal microbiota transplantation following allo-HCT reconstitutes microbiome diversity. Blood Adv (2018) 2(7):745–53. doi: 10.1182/bloodadvances.2018017731
Gorshein E, Wei C, Ambrosy S, Budney S, Vivas J, Shenkerman A, et al. Lactobacillus rhamnosus GG probiotic enteric regimen does not appreciably alter the gut microbiome or provide protection against GVHD after allogeneic hematopoietic stem cell transplantation. Clin Transplant (2017) 31(5):e12947. doi: 10.1111/ctr.12947
Al-Homsi AS, Feng Y, Duffner U, Al Malki MM, Goodyke A, Cole K, et al. Bortezomib for the prevention and treatment of graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Exp Hematol (2016) 44(9):771–7. doi: 10.1016/j.exphem.2016.05.005
Rager A, Frey N, Goldstein SC, Reshef R, Hexner EO, Loren A, et al. Inflammatory cytokine inhibition with combination daclizumab and infliximab for steroid-refractory acute GVHD. Bone Marrow Transplant (2011) 46(3):430–5. doi: 10.1038/bmt.2010.117
Lee SJ, Zahrieh D, Agura E, MacMillan ML, Maziarz RT, McCarthy PLJ, et al. Effect of up-front daclizumab when combined with steroids for the treatment of acute graft-versus-host disease: results of a randomized trial. Blood (2004) 104(5):1559–64. doi: 10.1182/blood-2004-03-0854
Antin JH, Weisdorf D, Neuberg D, Nicklow R, Clouthier S, Lee SJ, et al. Interleukin-1 blockade does not prevent acute graft-versus-host disease: results of a randomized, double-blind, placebo-controlled trial of interleukin-1 receptor antagonist in allogeneic bone marrow transplantation. Blood (2002) 100(10):3479–82. doi: 10.1182/blood-2002-03-0985
Hamadani M, Hofmeister CC, Jansak B, Phillips G, Elder P, Blum W, et al. Addition of infliximab to standard acute graft-versus-host disease prophylaxis following allogeneic peripheral blood cell transplantation. Biol Blood Marrow Transplant (2008) 14(7):783–9. doi: 10.1016/j.bbmt.2008.04.006
Martelli MF, Di Ianni M, Ruggeri L, Falzetti F, Carotti A, Terenzi A, et al. HLA-haploidentical transplantation with regulatory and conventional T-cell adoptive immunotherapy prevents acute leukemia relapse. Blood (2014) J124(4):638–44. doi: 10.1182/blood-2014-03-564401
Brunstein CG, Miller JS, Cao Q, McKenna DH, Hippen KL, Curtsinger J, et al. Infusion of ex vivo expanded T regulatory cells in adults transplanted with umbilical cord blood: safety profile and detection kinetics. Blood (2011) 117(3):1061–70. doi: 10.1182/blood-2010-07-293795
Di Ianni M, Falzetti F, Carotti A, Terenzi A, Castellino F, Bonifacio E, et al. Tregs prevent GVHD and promote immune reconstitution in HLA-haploidentical transplantation. Blood (2011) 117(14):3921–8. doi: 10.1182/blood-2010-10-311894elia
Copsel S, Wolf D, Komanduri KV, Levy RB. The promise of CD4 + FoxP3 + regulatory T-cell manipulation in vivo: applications for allogeneic hematopoietic stem cell transplantation. Haematologica (2019) 104(7):1309–21. doi: 10.3324/haematol.2018.198838
Kim B-S, Nishikii H, Baker J, Pierini A, Schneidawind D, Pan Y, et al. Treatment with agonistic DR3 antibody results in expansion of donor Tregs and reduced graft-versus-host disease. Blood (2015) 126(4):546–57. doi: 10.1182/blood-2015-04-637587
Malard F, Labopin M, Chevallier P, Guillaume T, Duquesne A, Rialland F, et al. Larger number of invariant natural killer T cells in PBSC allografts correlates with improved GVHD-free and progression-free survival. Blood (2016) 127(14):1828–35. doi: 10.1182/blood-2015-12-688739
Amarnath S, Foley JE, Farthing DE, Gress RE, Laurence A, Eckhaus MA, et al. Bone marrow-derived mesenchymal stromal cells harness purinergenic signaling to tolerize human Th1 cells in vivo. Stem Cells (2015) 33(4):1200–12. doi: 10.1002/stem.1934
Bruck F, Belle L, Lechanteur C, de Leval L, Hannon M, Dubois S, et al. Impact of bone marrow-derived mesenchymal stromal cells on experimental xenogeneic graft-versus-host disease. Cytotherapy (2013) 15(3):267–79. doi: 10.1016/j.jcyt.2012.09.003
Baron F, Lechanteur C, Willems E, Bruck F, Baudoux E, Seidel L, et al. Cotransplantation of mesenchymal stem cells might prevent death from graft-versus-host disease (GVHD) without abrogating graft-versus-tumor effects after HLA-mismatched allogeneic transplantation following nonmyeloablative conditioning. Biol Blood Marrow Transplant (2010) 16(6):838–47. doi: 10.1016/j.bbmt.2010.01.011
Gao L, Zhang Y, Hu B, Liu J, Kong P, Lou S, et al. Phase II Multicenter, Randomized, Double-Blind Controlled Study of Efficacy and Safety of Umbilical Cord-Derived Mesenchymal Stromal Cells in the Prophylaxis of Chronic Graft-Versus-Host Disease After HLA-Haploidentical Stem-Cell Transplantation. J Clin Oncol (2016) 34(24):2843–50. doi: 10.1200/JCO.2015.65.3642
Ning H, Yang F, Jiang M, Hu L, Feng K, Zhang J, et al. The correlation between cotransplantation of mesenchymal stem cells and higher recurrence rate in hematologic malignancy patients: outcome of a pilot clinical study. Leukemia (2008) 22(3):593–9. doi: 10.1038/sj.leu.2405090
Magenau JM, Goldstein SC, Peltier D, Soiffer RJ, Braun T, Pawarode A, et al. α(1)-Antitrypsin infusion for treatment of steroid-resistant acute graft-versus-host disease. Blood (2018) 131(12):1372–9. doi: 10.1182/blood-2017-11-815746
Tawara I, Sun Y, Lewis EC, Toubai T, Evers R, Nieves E, et al. Alpha-1-antitrypsin monotherapy reduces graft-versus-host disease after experimental allogeneic bone marrow transplantation. Proc Natl Acad Sci U S A (2012) 109(2):564–9. doi: 10.1073/pnas.1117665109
Stein-Thoeringer CK, Nichols KB, Lazrak A, Docampo MD, Slingerland AE, Slingerland JB, et al. Lactose drives Enterococcus expansion to promote graft-versus-host disease. Science (2019) 366(6469):1143–9. doi: 10.1126/science.aax3760
Bouazzaoui A, Huber E, Dan A, Al-Allaf FA, Pfirstinger J, Sprotte G, et al. Reduction of aGVHD using chicken antibodies directed against intestinal pathogens in a murine model. Blood (2017) 129(8):1052–5. doi: 10.1182/blood-2016-06-722538
Gerbitz A, Schultz M, Wilke A, Linde H-J, Schölmerich J, Andreesen R, et al. Probiotic effects on experimental graft-versus-host disease: let them eat yogurt. Blood (2004) 103(11):4365–7. doi: 10.1182/blood-2003-11-3769
Sadanand A, Newland JG, Bednarski JJ. Safety of Probiotics Among High-Risk Pediatric Hematopoietic Stem Cell Transplant Recipients. Infect Dis Ther (2019) 8(2):301–6. doi: 10.1007/s40121-019-0244-3
Schwartz M, Gluck M, Koon S. Norovirus gastroenteritis after fecal microbiota transplantation for treatment of Clostridium difficile infection despite asymptomatic donors and lack of sick contacts. Am J Gastroenterol (2013) 108(8):1367. doi: 10.1038/ajg.2013.164
DeFilipp Z, Bloom PP, Torres Soto M, Mansour MK, Sater MRA, Huntley MH, et al. Drug-Resistant E. coli Bacteremia Transmitted by Fecal Microbiota Transplant. N Engl J Med (2019) 381(21):2043–50. doi: 10.1056/NEJMoa1910437
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. doi: 10.1186/s40168-016-0178-x