Advances and challenges in immunotherapy for solid organ and hematopoietic stem cell transplantation

Science Translational Medicine

Volumn 7, Issue 280, 2015, Pages

  McDonald Hyman, Cameron ^a   Turka, Laurence A ^b,c   Blazar, Bruce R ^a  

^a UNIVERSITY OF MINNESOTA MEDICAL SCHOOL   (United States)

^b HARVARD MEDICAL SCHOOL   (United States)

^c MASSACHUSETTS GENERAL HOSPITAL   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

AZACITIDINE; CYCLOPHOSPHAMIDE; FINGOLIMOD; IBRUTINIB; IMMUNOMODULATING AGENT; INTERLEUKIN 2; KD 025; MARAVIROC; MONOCLONAL ANTIBODY; MSB 0010841; NN 8828; RAPAMYCIN; RITUXIMAB; RUXOLITINIB; SECUKINUMAB; SOTRASTAURIN; TMP 778; TMP 920; TOCILIZUMAB; TOFACITINIB; UNCLASSIFIED DRUG; USTEKINUMAB; VORINOSTAT;

B LYMPHOCYTE; CELL EXPANSION; CELL MIGRATION; CYTOKINE PRODUCTION; DRUG MECHANISM; DRUG RESPONSE; DRUG TARGETING; GRAFT REJECTION; GRAFT VERSUS HOST REACTION; HEMATOPOIETIC STEM CELL TRANSPLANTATION; HUMAN; IMMUNE RESPONSE; IMMUNOTHERAPY; NONHUMAN; ORGAN TRANSPLANTATION; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PRIORITY JOURNAL; PROPHYLAXIS; RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW; SIGNAL TRANSDUCTION; T LYMPHOCYTE; CLINICAL TRIAL (TOPIC);

CLINICAL TRIALS AS TOPIC; HEMATOPOIETIC STEM CELL TRANSPLANTATION; HUMANS; IMMUNOTHERAPY; ORGAN TRANSPLANTATION;

EID: 84925665321     PISSN: 19466234     EISSN: 19466242     Source Type: Journal    
DOI: 10.1126/scitranslmed.aaa6853     Document Type: Review

References (122)

1. M. Pasquini, X. Zhu, Current use and outcome of hematopoietic stem cell transplantation: CIBMTR Summary Slides, 2014; available at www.cibmtr.org (2014).
2. T. A. Gooley, J. W. Chien, S. A. Pergam, S. Hingorani, M. L. Sorror, M. Boeckh, P. J. Martin, B. M. Sandmaier, K. A. Marr, F. R. Appelbaum, R. Storb, G. B. McDonald, Reduced mortality after allogeneic hematopoietic-cell transplantation. N. Engl. J. Med. 363, 2091-2101 (2010).
3. J. R. Wingard, N. S. Majhail, R. Brazauskas, Z. Wang, K. A. Sobocinski, D. Jacobsohn, M. L. Sorror, M. M. Horowitz, B. Bolwell, J. D. Rizzo, G. Socié, Long-term survival and late deaths after allogeneic hematopoietic cell transplantation. J. Clin. Oncol. 29, 2230-2239 (2011).
4. L. A. Welniak, B. R. Blazar, W. J. Murphy, Immunobiology of allogeneic hematopoietic stem cell transplantation. Annu. Rev. Immunol. 25, 139-170 (2007).
5. B. R. Blazar, W. J. Murphy, M. Abedi, Advances in graft-versus-host disease biology and therapy. Nat. Rev. Immunol. 12, 443-458 (2012).
6. S. G. Holtan, M. Pasquini, D. J. Weisdorf, Acute graft-versus-host disease: A bench-to-bedside update. Blood 124, 363-373 (2014).
7. G. Piotti, A. Palmisano, U. Maggiore, C. Buzio, Vascular endothelium as a target of immune response in renal transplant rejection. Front. Immunol. 5, 505 (2014).
8. B. J. Nankivell, S. I. Alexander, Rejection of the kidney allograft. N. Engl. J. Med. 363, 1451-1462 (2010).
9. F. Issa, A. Schiopu, K. J. Wood, Role of T cells in graft rejection and transplantation tolerance. Expert Rev. Clin. Immunol. 6, 155-169 (2010).
10. + B cell depletion attenuates cardiac allograft vasculopathy in cyclosporine-treated monkeys. J. Clin. Invest. 120, 1275-1284 (2010).
11. A. Loupy, G. Hill, S. Jordan, The impact of donor-specific anti-HLA antibodies on late kidney allograft failure. Nat. Rev. Nephrol. 8, 348-357 (2012).
12. K. A. Markey, K. P. A. MacDonald, G. R. Hill, The biology of graft-versus-host disease: Experimental systems instructing clinical practice. Blood 124, 354-362 (2014).
13. A. M. Cueto-Manzano, L. E. Morales-Buenrostro, L. González-Espinoza, N. González-Tableros, F. Martin-del-Campo, R. Correa-Rotter, I. Valera, J. Alberú, Markers of inflammation before and after renal transplantation. Transplantation 80, 47-51 (2005).
14. + cells. J. Immunol. 187, 5764-5771 (2011).
15. I. Tawara, M. Koyama, C. Liu, T. Toubai, D. Thomas, R. Evers, P. Chockley, E. Nieves, Y. Sun, K. P. Lowler, C. Malter, N. Nishimoto, G. R. Hill, P. Reddy, Interleukin-6 modulates graft-versus-host responses after experimental allogeneic bone marrow transplantation. Clin. Cancer Res. 17, 77-88 (2011).
16. G. A. Kennedy, A. Varelias, S. Vuckovic, L. Le Texier, K. H. Gartlan, P. Zhang, G. Thomas, L. Anderson, G. Boyle, N. Cloonan, J. Leach, E. Sturgeon, J. Avery, S. D. Olver, M. Lor, A. K. Misra, C. Hutchins, A. J. Morton, S. T. S. Durrant, E. Subramoniapillai, J. P. Butler, C. I. Curley, K. P. A. MacDonald, S.-K. Tey, G. R. Hill, 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. 15, 1451-1459 (2014).
17. G. W. Kim, N. R. Lee, R. H. Pi, Y. S. Lim, Y. M. Lee, J. M. Lee, H. S. Jeong, S. H. Chung, IL-6 inhibitors for treatment of rheumatoid arthritis: Past, present, and future. Arch. Pharm. Res., in press.
18. D. K. De Vries, J. H. N. Lindeman, D. Tsikas, E. De Heer, A. Roos, J. W. De Fijter, A. G. Baranski, J. Van Pelt, A. F. M. Schaapherder, Early renal ischemia-reperfusion injury in humans is dominated by IL-6 release from the allograft. Am. J. Transplant. 9, 1574-1584 (2009).
19. R. Das, R. Komorowski, M. J. Hessner, H. Subramanian, C. S. Huettner, D. Cua, W. R. Drobyski, Blockade of interleukin-23 signaling results in targeted protection of the colon and allows for separation of graft-versus-host and graft-versus-leukemia responses. Blood 115, 5249-5258 (2010).
20. E. Williamson, P. Garside, J. A. Bradley, I. A. More, A. M. Mowat, Neutralizing IL-12 during induction of murine acute graft-versus-host disease polarizes the cytokine profile toward a Th2-type alloimmune response and confers long term protection from disease. J. Immunol. 159, 1208-1215 (1997).
21. J. Pidala, L. Perez, F. Beato, C. Anasetti, Ustekinumab demonstrates activity in glucocorticoid-refractory acute GVHD. Bone Marrow Transplant. 47, 747-748 (2012).
22. I. B. McInnes, A. Kavanaugh, A. B. Gottlieb, L. Puig, P. Rahman, C. Ritchlin, C. Brodmerkel, S. Li, Y. Wang, A. M. Mendelsohn, M. K. Doyle; PSUMMIT 1 Study Group, Efficacy and safety of ustekinumab in patients with active psoriatic arthritis: 1 year results of the phase 3, multicentre, double-blind, placebo-controlled PSUMMIT 1 trial. Lancet 382, 780-789 (2013).
23. M. Murai, H. Yoneyama, T. Ezaki, M. Suematsu, Y. Terashima, A. Harada, H. Hamada, H. Asakura, H. Ishikawa, K. Matsushima, Peyer's patch is the essential site in initiating murine acute and lethal graft-versus-host reaction. Nat. Immunol. 4, 154-160 (2003).
24. + T lymphocytes in the pathogenesis of liver injury in graft-versus-host disease. J. Clin. Invest. 104, 49-57 (1999).
25. K. Shahin, M. Sartor, D. N. J. Hart, K. F. Bradstock, Alterations in chemokine receptor CCR5 expression on blood dendritic cells correlate with acute graft-versus-host disease. Transplantation 96, 753-762 (2013).
26. R. Reshef, S. M. Luger, E. O. Hexner, A. W. Loren, N. V. Frey, S. D. Nasta, S. C. Goldstein, E. A. Stadtmauer, J. Smith, S. Bailey, R. Mick, D. F. Heitjan, S. G. Emerson, J. A. Hoxie, R. H. Vonderheide, D. L. Porter, Blockade of lymphocyte chemotaxis in visceral graft-versus-host disease. N. Engl. J. Med. 367, 135-145 (2012).
27. C. A. Wysocki, S. B. Burkett, A. Panoskaltsis-Mortari, S. L. Kirby, A. D. Luster, K. McKinnon, B. R. Blazar, J. S. Serody, Differential roles for CCR5 expression on donor T cells during graft-versus-host disease based on pretransplant conditioning. J. Immunol. 173, 845-854 (2004).
28. A. H. Dalloul, B-cell-mediated strategies to fight chronic allograft rejection. Front. Immunol. 4, 444-452 (2013).
29. H.-H. Ma, J. Ziegler, C. Li, A. Sepulveda, A. Bedeir, J. Grandis, S. Lentzsch, M. Y. Mapara, Sequential activation of inflammatory signaling pathways during graft-versus-host disease (GVHD): Early role for STAT1 and STAT3. Cell. Immunol. 268, 37-46 (2011).
30. S. Spoerl, N. R. Mathew, M. Bscheider, A. Schmitt-Graeff, S. Chen, T. Mueller, M. Verbeek, J. Fischer, V. Otten, M. Schmickl, K. Maas-Bauer, J. Finke, C. Peschel, J. Duyster, H. Poeck, R. Zeiser, N. von Bubnoff, Activity of therapeutic JAK 1/2 blockade in graft-versus-host disease. Blood 123, 3832-3842 (2014).
31. S. Verstovsek, R. A. Mesa, J. Gotlib, R. S. Levy, V. Gupta, J. F. DiPersio, J. V. Catalano, M. W. Deininger, C. B. Miller, R. T. Silver, M. Talpaz, E. F. Winton, J. H. Harvey, M. O. Arcasoy, E. O. Hexner, R. M. Lyons, A. Raza, K. Vaddi, W. Sun, W. Peng, V. Sandor, H. Kantarjian, Three-year efficacy, overall survival, and safety of ruxolitinib therapy in patients with myelofibrosis from the COMFORT-I study. Haematologica, in press.
32. A.-K. Hechinger, B. A. H. Smith, R. Flynn, K. Hanke, C. McDonald-Hyman, P. A. Taylor, D. Pfeifer, B. Hackanson, F. Leonhardt, G. Prinz, H. Dierbach, A. Schmitt-Graeff, J. Kovarik, B. R. Blazar, R. Zeiser, Therapeutic activity of multiple common γ-chain cytokine inhibition in acute and chronic GvHD. Blood 125, 570-580 (2014).
33. D. C. Borie, P. S. Changelian, M. J. Larson, M.-S. Si, R. Paniagua, J. P. Higgins, B. Holm, A. Campbell, M. Lau, S. Zhang, M. G. Flores, G. Rousvoal, J. Hawkins, D. A. Ball, E. M. Kudlacz, W. H. Brissette, E. A. Elliott, B. A. Reitz, R. E. Morris, Immunosuppression by the JAK3 Inhibitor CP-690,550 delays rejection and significantly prolongs kidney allograft survival in nonhuman primates. Transplantation 79, 791-801 (2005).
34. D. C. Borie, M. J. Larson, M. G. Flores, A. Campbell, G. Rousvoal, S. Zhang, J. P. Higgins, D. J. Ball, E. M. Kudlacz, W. H. Brissette, E. A. Elliott, B. A. Reitz, P. S. Changelian, Combined use of the JAK3 Inhibitor CP-690,550 with mycophenolate mofetil to prevent kidney allograft rejection in nonhuman primates. Transplantation 80, 1756-1764 (2005).
35. E. Van Gurp, W. Weimar, R. Gaston, D. Brennan, R. Mendez, J. Pirsch, S. Swan, M. D. Pescovitz, G. Ni, C. Wang, S. Krishnaswami, V. Chow, G. Chan, Phase 1 dose-escalation study of CP-690 550 in stable renal allograft recipients: Preliminary findings of safety, tolerability, effects on lymphocyte subsets and pharmacokinetics. Am. J. Transplant. 8, 1711-1718 (2008).
36. F. Vincenti, H. Tedesco Silva, S. Busque, P. O'Connell, J. Friedewald, D. Cibrik, K. Budde, A. Yoshida, S. Cohney, W. Weimar, Y. S. Kim, N. Lawendy, S. P. Lan, E. Kudlacz, S. Krishnaswami, G. Chan, Randomized phase 2b trial of tofacitinib (CP-690,550) in de novo kidney transplant patients: Efficacy, renal function and safety at 1 year. Am. J. Transplant. 12, 2446-2456 (2012).
37. J. Gomez-Rodriguez, E. A. Wohlfert, R. Handon, F. Meylan, J. Z. Wu, S. M. Anderson, M. R. Kirby, Y. Belkaid, P. L. Schwartzberg, Itk-mediated integration of T cell receptor and cytokine signaling regulates the balance between Th17 and regulatory T cells. J. Exp. Med. 211, 529-543 (2014).
38. S. E. M. Herman, A. L. Gordon, E. Hertlein, A. Ramanunni, X. Zhang, S. Jaglowski, J. Flynn, J. Jones, K. A. Blum, J. J. Buggy, A. Hamdy, A. J. Johnson, J. C. Byrd, Bruton tyrosine kinase represents a promising therapeutic target for treatment of chronic lymphocytic leukemia and is effectively targeted by PCI-32765. Blood 117, 6287-6296 (2011).
39. J. A. Dubovsky, R. Flynn, J. Du, B. K. Harrington, Y. Zhong, B. Kaffenberger, C. Yang, W. H. Towns, A. Lehman, A. J. Johnson, N. Muthusamy, S. M. Devine, S. Jaglowski, J. S. Serody, W. J. Murphy, D. H. Munn, L. Luznik, G. R. Hill, H. K. Wong, K. K. P. MacDonald, I. Maillard, J. Koreth, L. Elias, C. Cutler, R. J. Soiffer, J. H. Antin, J. Ritz, A. Panoskaltsis-Mortari, J. C. Byrd, B. R. Blazar, Ibrutinib treatment ameliorates murine chronic graft-versus-host disease. J. Clin. Invest. 124, 4867-4876 (2014).
40. J. A. Dubovsky, K. A. Beckwith, G. Natarajan, J. A. Woyach, S. Jaglowski, Y. Zhong, J. D. Hessler, T.-M. Liu, B. Y. Chang, K. M. Larkin, M. R. Stefanovski, D. L. Chappell, F. W. Frissora, L. L. Smith, K. A. Smucker, J. M. Flynn, J. A. Jones, L. A. Andritsos, K. Maddocks, A. M. Lehman, R. Furman, J. Sharman, A. Mishra, M. A. Caligiuri, A. R. Satoskar, J. J. Buggy, N. Muthusamy, A. J. Johnson, J. C. Byrd, Ibrutinib is an irreversible molecular inhibitor of ITK driving a Th1-selective pressure in T lymphocytes. Blood 122, 2539-2549 (2013).
41. J. C. Byrd, J. R. Brown, S. O'Brien, J. C. Barrientos, N. E. Kay, N. M. Reddy, S. Coutre, C. S. Tam, S. P. Mulligan, U. Jaeger, S. Devereux, P. M. Barr, R. R. Furman, T. J. Kipps, F. Cymbalista, C. Pocock, P. Thornton, F. Caligaris-Cappio, T. Robak, J. Delgado, S. J. Schuster, M. Montillo, A. Schuh, S. de Vos, D. Gill, A. Bloor, C. Dearden, C. Moreno, J. J. Jones, A. D. Chu, M. Fardis, J. McGreivy, F. Clow, D. F. James, P. Hillmen; RESONATE Investigators, Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N. Engl. J. Med. 371, 213-223 (2014).
42. G. R. Russ, H. Tedesco-Silva, D. R. Kuypers, S. Cohney, R. M. Langer, O. Witzke, J. Eris, C. Sommerer, B. von Zur-Mühlen, E. S. Woodle, J. Gill, J. Ng, J. Klupp, L. Chodoff, K. Budde, Efficacy of sotrastaurin plus tacrolimus after de novo kidney transplantation: Randomized, phase II trial results. Am. J. Transplant. 13, 1746-1756 (2013).
43. K. M. K. Haarberg, J. Li, J. Heinrichs, D. Wang, C. Liu, C. C. Bronk, K. Kaosaard, A. M. Owyang, S. Holland, E. Masuda, K. Tso, B. R. Blazar, C. Anasetti, A. A. Beg, X.-Z. Yu, Pharmacologic inhibition of PKCα and PKCθ prevents GVHD while preserving GVL activity in mice. Blood 122, 2500-2511 (2013).
44. G. Socié, J. Ritz, Current issues in chronic graft-versus-host disease. Blood 124, 374-384 (2014).
45. H. F. Johnston, Y. Xu, J. J. Racine, K. Cassady, X. Ni, T. Wu, A. Chan, S. Forman, D. Zeng, Administration of anti-CD20 mAb is highly effective in preventing but ineffective in treating chronic graft-versus-host disease while preserving strong graft-versus-leukemia effects. Biol. Blood Marrow Transplant. 20, 1089-1103 (2014).
46. S. Arai, B. Sahaf, B. Narasimhan, G. L. Chen, C. D. Jones, R. Lowsky, J. A. Shizuru, L. J. Johnston, G. G. Laport, W.-K. Weng, J. E. Benjamin, J. Schaenman, J. Brown, J. Ramirez, J. L. Zehnder, R. S. Negrin, D. B. Miklos, Prophylactic rituximab after allogeneic transplantation decreases B-cell alloimmunity with low chronic GVHD incidence. Blood 119, 6145-6154 (2012).
47. C. Cutler, H. T. Kim, B. Bindra, S. Sarantopoulos, V. T. Ho, Y.-B. Chen, J. Rosenblatt, S. McDonough, P. Watanaboonyongcharoen, P. Armand, J. Koreth, B. Glotzbecker, E. Alyea, B. R. Blazar, R. J. Soiffer, J. Ritz, J. H. Antin, Rituximab prophylaxis prevents corticosteroid-requiring chronic GVHD after allogeneic peripheral blood stem cell transplantation: Results of a phase 2 trial. Blood 122, 1510-1517 (2013).
48. A. N. R. Barnett, V. G. Hadjianastassiou, N. Mamode, Rituximab in renal transplantation. Transpl. Int. 26, 563-575 (2013).
49. D. Hanahan, R. A. Weinberg, The hallmarks of cancer. Cell 100, 57-70 (2000).
50. K. Sun, L. A. Welniak, A. Panoskaltsis-Mortari, M. J. O'Shaughnessy, H. Liu, I. Barao, W. Riordan, R. Sitcheran, C. Wysocki, J. S. Serody, B. R. Blazar, T. J. Sayers, W. J. Murphy, Inhibition of acute graft-versus-host disease with retention of graft-versus-tumor effects by the proteasome inhibitor bortezomib. Proc. Natl. Acad. Sci. U.S.A. 101, 8120-8125 (2004).
51. C. C. S. Pai, H.-H. Hsiao, K. Sun, M. Chen, T. Hagino, J. Tellez, C. Mall, B. R. Blazar, A. Monjazeb, M. Abedi, W. J. Murphy, Therapeutic benefit of bortezomib on acute graft-versus-host disease is tissue specific and is associated with interleukin-6 levels. Biol. Blood Marrow Transplant. 20, 1899-1904 (2014).
52. C. C. S. Pai, M. Chen, A. Mirsoian, S. K. Grossenbacher, J. Tellez, E. Ames, K. Sun, J. Jagdeo, B. R. Blazar, W. J. Murphy, M. Abedi, Treatment of chronic graft-versus-host disease with bortezomib. Blood 124, 1677-1688 (2014).
53. A. F. Herrera, H. T. Kim, B. Bindra, K. T. Jones, E. P. Alyea III, P. Armand, C. S. Cutler, V. T. Ho, S. Nikiforow, B. R. Blazar, J. Ritz, J. H. Antin, R. J. Soiffer, J. Koreth, A phase II study of bortezomib plus prednisone for initial therapy of chronic graft-versus-host disease. Biol. Blood Marrow Transplant. 20, 1737-1743 (2014).
54. R. Sberro-Soussan, J. Zuber, C. Suberbielle-Boissel, S. Candon, F. Martinez, R. Snanoudj, M. Rabant, N. Pallet, D. Nochy, D. Anglicheau, M. Leruez, A. Loupy, E. Thervet, O. Hermine, C. Legendre, Bortezomib as the sole post-renal transplantation desensitization agent does not decrease donor-specific anti-HLA antibodies. Am. J. Transplant. 10, 681-686 (2010).
55. N. Ohkura, Y. Kitagawa, S. Sakaguchi, Development and maintenance of regulatory T cells. Immunity 38, 414-423 (2013).
56. K. Matsuoka, J. Koreth, H. T. Kim, G. Bascug, S. McDonough, Y. Kawano, K. Murase, C. Cutler, V. T. Ho, E. P. Alyea, P. Armand, B. R. Blazar, J. H. Antin, R. J. Soiffer, J. Ritz, Low-dose interleukin-2 therapy restores regulatory T cell homeostasis in patients with chronic graft-versus-host disease. Sci. Transl. Med. 5, 179ra143 (2013).
57. + regulatory T cells. Blood 118, 2342-2350 (2011).
58. O. C. Goodyear, M. Dennis, N. Y. Jilani, J. Loke, S. Siddique, G. Ryan, J. Nunnick, R. Khanum, M. Raghavan, M. Cook, J. A. Snowden, M. Griffiths, N. Russell, J. Yin, C. Crawley, G. Cook, P. Vyas, P. Moss, R. Malladi, C. F. Craddock, Azacitidine augments expansion of regulatory T cells after allogeneic stem cell transplantation in patients with acute myeloid leukemia (AML). Blood 119, 3361-3369 (2012).
59. J. Choi, J. Ritchey, J. L. Prior, M. Holt, W. D. Shannon, E. Deych, D. R. Piwnica-Worms, J. F. DiPersio, In vivo administration of hypomethylating agents mitigate graft-versus-host disease without sacrificing graft-versus-leukemia. Blood 116, 129-139 (2010).
60. + regulatory T cells. Nat. Rev. Drug Discov. 8, 969-981 (2009).
61. R. Tao, E. F. de Zoeten, E. Ozkaynak, C. Chen, L. Wang, P. M. Porrett, B. Li, L. A. Turka, E. N. Olson, M. I. Greene, A. D. Wells, W. W. Hancock, Deacetylase inhibition promotes the generation and function of regulatory T cells. Nat. Med. 13, 1299-1307 (2007).
62. S. W. Choi, T. Braun, L. Chang, J. L. M. Ferrara, A. Pawarode, J. M. Magenau, G. Hou, J. H. Beumer, J. E. Levine, S. Goldstein, D. R. Couriel, K. Stockerl-Goldstein, O. I. Krijanovski, C. Kitko, G. A. Yanik, M. H. Lehmann, I. Tawara, Y. Sun, S. Paczesny, M. Y. Mapara, C. A. Dinarello, J. F. DiPersio, P. Reddy, 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. 15, 87-95 (2014).
63. S. W. Choi, E. Gatza, G. Hou, Y. Sun, J. Whitfield, Y. Song, K. Oravecz-Wilson, I. Tawara, C. A. Dinarello, P. Reddy, Histone deacetylase inhibition regulates inflammation and enhances Tregs after allogeneic hematopoietic cell transplantation in humans. Blood 125, 815-819 (2015).
64. C. G. Kanakry, S. Ganguly, M. Zahurak, J. Bolaños-Meade, C. Thoburn, B. Perkins, E. J. Fuchs, R. J. Jones, A. D. Hess, L. Luznik, Aldehyde dehydrogenase expression drives human regulatory T cell resistance to posttransplantation cyclophosphamide. Sci. Transl. Med. 5, 211ra157 (2013).
65. C. G. Kanakry, P. V. O'Donnell, T. Furlong, M. J. de Lima, W. Wei, M. Medeot, M. Mielcarek, R. E. Champlin, R. J. Jones, P. F. Thall, B. S. Andersson, L. Luznik, Multi-institutional study of post-transplantation cyclophosphamide as single-agent graft-versus-host disease prophylaxis after allogeneic bone marrow transplantation using myeloablative busulfan and fludarabine conditioning. J. Clin. Oncol. 32, 3497-3505 (2014).
66. L. Luznik, P. V. O'Donnell, E. J. Fuchs, Post-transplantation cyclophosphamide for tolerance induction in HLA-haploidentical bone marrow transplantation. Semin. Oncol. 39, 683-693 (2012).
67. + regulatory T cells preserve graft-versus-tumor activity while inhibiting graft-versus-host disease after bone marrow transplantation. Nat. Med. 9, 1144-1150 (2003).
68. + immune regulatory cells inhibits graft-versus-host disease lethality. Blood 99, 3493-3499 (2002).
69. P. Sagoo, G. Lombardi, R. I. Lechler, Relevance of regulatory T cell promotion of donor-specific tolerance in solid organ transplantation. Front. Immunol. 3, 184-209 (2012).
70. E. C. Guinan, V. A. Boussiotis, D. Neuberg, L. L. Brennan, N. Hirano, L. M. Nadler, J. G. Gribben, Transplantation of anergic histoincompatible bone marrow allografts. N. Engl. J. Med. 340, 1704-1714 (1999).
71. J. K. Davies, L. M. Nadler, E. C. Guinan, Expansion of allospecific regulatory T cells after anergized, mismatched bone marrow transplantation. Sci. Transl. Med. 1, 1ra3 (2009).
72. C. G. Brunstein, J. S. Miller, Q. Cao, D. H. McKenna, K. L. Hippen, J. Curtsinger, T. DeFor, B. L. Levine, C. H. June, P. Rubinstein, P. B. McGlave, B. R. Blazar, J. E. Wagner, Infusion of ex vivo expanded T regulatory cells in adults transplanted with umbilical cord blood: Safety profile and detection kinetics. Blood 117, 1061-1070 (2011).
73. M. F. Martelli, M. Di Ianni, L. Ruggeri, F. Falzetti, A. Carotti, A. Terenzi, A. Pierini, M. S. Massei, L. Amico, E. Urbani, B. Del Papa, T. Zei, R. Iacucci Ostini, D. Cecchini, R. Tognellini, Y. Reisner, F. Aversa, B. Falini, A. Velardi, HLA-haploidentical transplantation with regulatory and conventional T-cell adoptive immunotherapy prevents acute leukemia relapse. Blood 124, 638-644 (2014).
74. N. Gagliani, C. F. Magnani, S. Huber, M. E. Gianolini, M. Pala, P. Licona-Limon, B. Guo, D. B. R. Herbert, A. Bulfone, F. Trentini, C. Di Serio, R. Bacchetta, M. Andreani, L. Brockmann, S. Gregori, R. A. Flavell, M.-G. Roncarolo, Coexpression of CD49b and LAG-3 identifies human and mouse T regulatory type 1 cells. Nat. Med. 19, 739-746 (2013).
75. R. Bacchetta, B. Lucarelli, C. Sartirana, S. Gregori, M. T. Lupo Stanghellini, P. Miqueu, S. Tomiuk, M. Hernandez-Fuentes, M. E. Gianolini, R. Greco, M. Bernardi, E. Zappone, S. Rossini, U. Janssen, A. Ambrosi, M. Salomoni, J. Peccatori, F. Ciceri, M.-G. Roncarolo, Immunological outcome in haploidentical-HSC transplanted patients treated with IL-10-anergized donor T cells. Front. Immunol. 5, 16-30 (2014).
76. B. Amorin, A. P. Alegretti, V. Valim, A. Pezzi, A. M. Laureano, M. A. L. da Silva, A. Wieck, L. Silla, Mesenchymal stem cell therapy and acute graft-versus-host disease: A review. Hum. Cell 27, 137-150 (2014).
77. P. Kebriaei, L. Isola, E. Bahceci, K. Holland, S. Rowley, J. McGuirk, M. Devetten, J. Jansen, R. Herzig, M. Schuster, R. Monroy, J. Uberti, Adult human mesenchymal stem cells added to corticosteroid therapy for the treatment of acute graft-versus-host disease. Biol. Blood Marrow Transplant. 15, 804-811 (2009).
78. J. Y. Weng, X. Du, S. X. Geng, Y. W. Peng, Z. Wang, Z. S. Lu, S. J. Wu, C. W. Luo, R. Guo, W. Ling, C. X. Deng, P. J. Liao, A. P. Xiang, Mesenchymal stem cell as salvage treatment for refractory chronic GVHD. Bone Marrow Transplant. 45, 1732-1740 (2010).
79. K. Zhao, R. Lou, F. Huang, Y. Peng, Z. Jiang, K. Huang, X. Wu, Y. Zhang, Z. Fan, H. Zhou, C. Liu, Y. Xiao, J. Sun, Y. Li, P. Xiang, Q. Liu, Immunomodulation effects of mesenchymal stromal cells on acute graft-versus-host disease after hematopoietic stem cell transplantation. Biol. Blood Marrow Transplant. 21, 97-104 (2014).
80. J. Galipeau, The mesenchymal stromal cells dilemma - Does a negative phase III trial of random donor mesenchymal stromal cells in steroid-resistant graft-versus-host disease represent a death knell or a bump in the road? Cytotherapy 15, 2-8 (2013).
81. J. A. Hutchinson, P. Riquelme, B. Sawitzki, S. Tomiuk, P. Miqueu, M. Zuhayra, H. H. Oberg, A. Pascher, U. Lützen, U. Janßen, C. Broichhausen, L. Renders, F. Thaiss, E. Scheuermann, E. Henze, H.-D. Volk, L. Chatenoud, R. I. Lechler, K. J. Wood, D. Kabelitz, H. J. Schlitt, E. K. Geissler, F. Fändrich, Cutting edge: Immunological consequences and trafficking of human regulatory macrophages administered to renal transplant recipients. J. Immunol. 187, 2072-2078 (2011).
82. J. Ashton-Chess, G. Blancho, An in vitro evaluation of the potential suitability of peripheral blood CD14+ and bone marrow CD34+-derived dendritic cells for a tolerance inducing regimen in the primate. J. Immunol. Methods 297, 237-252 (2005).
83. D. Raïch-Regué, M. Glancy, A. W. Thomson, Regulatory dendritic cell therapy: From rodents to clinical application. Immunol. Lett. 161, 216-221 (2014).
84. K. Sato, N. Yamashita, N. Yamashita, M. Baba, T. Matsuyama, Regulatory dendritic cells protect mice from murine acute graft-versus-host disease and leukemia relapse. Immunity 18, 367-379 (2003).
85. S. T. Ildstad, D. H. Sachs, Reconstitution with syngeneic plus allogeneic or xenogeneic bone marrow leads to specific acceptance of allografts or xenografts. Nature 307, 168-170 (1984).
86. T. Kawai, D. H. Sachs, M. Sykes, A. B. Cosimi; Immune Tolerance Network, HLA-mismatched renal transplantation without maintenance immunosuppression. N. Engl. J. Med. 368, 1850-1852 (2013).
87. J. Leventhal, M. Abecassis, J. Miller, L. Gallon, K. Ravindra, D. J. Tollerud, B. King, M. J. Elliott, G. Herzig, R. Herzig, S. T. Ildstad, Chimerism and tolerance without GVHD or engraftment syndrome in HLA-mismatched combined kidney and hematopoietic stem cell transplantation. Sci. Transl. Med. 4, 124ra128 (2012).
88. A. M. Hanash, L. W. Kappel, N. L. Yim, R. A. Nejat, G. L. Goldberg, O. M. Smith, U. K. Rao, L. Dykstra, I.-K. Na, A. M. Holland, J. A. Dudakov, C. Liu, G. F. Murphy, W. J. Leonard, G. Heller, M. R. M. van den Brink, Abrogation of donor T-cell IL-21 signaling leads to tissue-specific modulation of immunity and separation of GVHD from GVL. Blood 118, 446-455 (2011).
89. R. Flynn, J. Du, R. G. Veenstra, D. K. Reichenbach, A. Panoskaltsis-Mortari, P. A. Taylor, G. J. Freeman, J. S. Serody, W. J. Murphy, D. H. Munn, S. Sarantopoulos, L. Luznik, I. Maillard, J. Koreth, C. Cutler, R. J. Soiffer, J. H. Antin, J. Ritz, J. A. Dubovsky, J. C. Byrd, K. P. MacDonald, G. R. Hill, B. R. Blazar, Increased T follicular helper cells and germinal center B cells are required for cGVHD and bronchiolitis obliterans. Blood 123, 3988-3998 (2014).
90. P. S. Biswas, S. Gupta, E. Chang, L. Song, R. A. Stirzaker, J. K. Liao, G. Bhagat, A. B. Pernis, Phosphorylation of IRF4 by ROCK2 regulates IL-17 and IL-21 production and the development of autoimmunity in mice. J. Clin. Invest. 120, 3280-3295 (2010).
91. R. S. Knipe, A. M. Tager, J. K. Liao, The Rho kinases: Critical mediators of multiple profibrotic processes and rational targets for new therapies for pulmonary fibrosis. Pharmacol. Rev. 67, 103-117 (2015).
92. A. Zanin-Zhorov, J. M. Weiss, M. S. Nyuydzefe, W. Chen, J. U. Scher, R. Mo, D. Depoil, N. Rao, B. Liu, J. Wei, S. Lucas, M. Koslow, M. Roche, O. Schueller, S. Weiss, M. V. Poyurovsky, J. Tonra, K. L. Hippen, M. L. Dustin, B. R. Blazar, C.-j. Liu, S. D. Waksal, Selective oral ROCK2 inhibitor down-regulates IL-21 and IL-17 secretion in human T cells via STAT3-dependent mechanism. Proc. Natl. Acad. Sci. U.S.A. 111, 16814-16819 (2014).
93. S. Xiao, N. Yosef, J. Yang, Y. Wang, L. Zhou, C. Zhu, C. Wu, E. Baloglu, D. Schmidt, R. Ramesh, M. Lobera, M. S. Sundrud, P.-Y. Tsai, Z. Xiang, J. Wang, Y. Xu, X. Lin, K. Kretschmer, P. B. Rahl, R. A. Young, Z. Zhong, D. A. Hafler, A. Regev, S. Ghosh, A. Marson, V. K. Kuchroo, Small-molecule RORγt antagonists inhibit T helper 17 cell transcriptional network by divergent mechanisms. Immunity 40, 477-489 (2014).
94. D. D. Pinschewer, A. F. Ochsenbein, B. Odermatt, V. Brinkmann, H. Hengartner, R. M. Zinkernagel, FTY720 immunosuppression impairs effector T cell peripheral homing without affecting induction, expansion, and memory. J. Immunol. 164, 5761-5770 (2000).
95. Y.-M. Kim, T. Sachs, W. Asavaroengchai, R. Bronson, M. Sykes, Graft-versus-host disease can be separated from graft-versus-lymphoma effects by control of lymphocyte trafficking with FTY720. J. Clin. Invest. 111, 659-669 (2003).
96. P. A. Taylor, M. J. Ehrhardt, C. J. Lees, J. Tolar, B. J. Weigel, A. Panoskaltsis-Mortari, J. S. Serody, V. Brinkmann, B. R. Blazar, Insights into the mechanism of FTY720 and compatibility with regulatory T cells for the inhibition of graft-versus-host disease (GVHD). Blood 110, 3480-3488 (2007).
97. K. Budde, M. Schütz, P. Glander, H. Peters, J. Waiser, L. Liefeldt, H.-H. Neumayer, T. Böhler, FTY720 (fingolimod) in renal transplantation. Clin. Transplant. 20 (Suppl. 17), 17-24 (2006).
98. L. A. Turka, P. S. Linsley, H. Lin, W. Brady, J. M. Leiden, R. Q. Wei, M. L. Gibson, X.-G. Zheng, S. Myrdal, D. Gordon, T-cell activation by the CD28 ligand B7 is required for cardiac allograft rejection in vivo. Proc. Natl. Acad. Sci. U.S.A. 89, 11102-11105 (1992).
99. B. Blazar, P. Taylor, P. Linsley, D. Vallera, 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 83, 3815-3825 (1994).
100. D. T. Koura, J. T. Horan, A. A. Langston, M. Qayed, A. Mehta, H. J. Khoury, R. D. Harvey, Y. Suessmuth, C. Couture, J. Carr, A. Grizzle, H. R. Johnson, J. A. Cheeseman, J. A. Conger, J. Robertson, L. Stempora, B. E. Johnson, A. Garrett, A. D. Kirk, C. P. Larsen, E. K. Waller, L. S. Kean, In vivo t cell costimulation blockade with abatacept for acute graft-versus-host disease prevention: A first-in-disease trial. Biol. Blood Marrow Transplant. 19, 1638-1649 (2013).
101. C. Mary, F. Coulon, N. Poirier, N. Dilek, B. Martinet, G. Blancho, B. Vanhove, Antagonist properties of monoclonal antibodies targeting human CD28: Role of valency and the heavy-chain constant domain. MAbs 5, 47-55 (2013).
102. N. Poirier, C. Mary, N. Dilek, J. Hervouet, D. Minault, G. Blancho, B. Vanhove, Preclinical efficacy and immunological safety of FR104, an antagonist anti-CD28 monovalent Fab' antibody. Am. J. Transplant. 12, 2630-2640 (2012).
103. S. Blüml, K. McKeever, R. Ettinger, J. Smolen, R. Herbst, B-cell targeted therapeutics in clinical development. Arthritis Res. Ther. 15, S4 (2013).
104. H. J. Choi, J. J. Lee, D. H. Kim, M. K. Kim, H. J. Lee, A. Y. Ko, H. J. Kang, C. Park, W. R. Wee, Blockade of CD40-CD154 costimulatory pathway promotes long-term survival of full-thickness porcine corneal grafts in nonhuman primates: Clinically applicable xenocorneal transplantation. Am. J. Transplant. 15, 628-641 (2015).
105. K. Hock, N. Pilat, U. Baranyi, B. Mahr, M. Gattringer, C. Klaus, T. Wekerle, Donor CD4 T cells trigger costimulation blockade-resistant donor bone marrow rejection through bystander activation requiring IL-6. Am. J. Transplant. 14, 2011-2022 (2014).
106. W. H. Kwan, W. van der Touw, E. Paz-Artal, M. O. Li, P. S. Heeger, Signaling through C5a receptor and C3a receptor diminishes function of murine natural regulatory T cells. J. Exp. Med. 210, 257-268 (2013).
107. P. N. Lalli, M. G. Strainic, M. Yang, F. Lin, M. E. Medof, P. S. Heeger, Locally produced C5a binds to T cell-expressed C5aR to enhance effector T-cell expansion by limiting antigen-induced apoptosis. Blood 112, 1759-1766 (2008).
108. B. E. Lonze, N. N. Dagher, C. E. Simpkins, D. L. Segev, A. L. Singer, S. Cohney, N. Alachkar, R. A. Montgomery, Eculizumab prevents recurrence of antiphospholipid antibody syndrome (APS) in renal allografts. Transplantation 90, 178 (2010).
109. L. K. Jasperson, C. Bucher, A. Panoskaltsis-Mortari, A. L. Mellor, D. H. Munn, B. R. Blazar, Inducing the tryptophan catabolic pathway, indoleamine 2,3-dioxygenase (IDO), for suppression of graft-versus-host disease (GVHD) lethality. Blood 114, 5062-5070 (2009).
110. + T helper cells is controlled by the transcription factor Eos. Immunity 38, 998-1012 (2013).
111. L. C. Cerchietti, A. F. Ghetu, X. Zhu, G. F. Da Silva, Z. Shijun, M. Matthews, K. L. Bunting, J. M. Polo, C. Farès, C. H. Arrowsmith, S. N. Yang, M. Garcia, A. Coop, A. D. MacKerell, G. G. Privé, A. Melnick, A small molecule inhibitor of BCL6 kills DLBCL cells in vitro and in vivo. Cancer Cell 17, 400-411 (2010).
112. M. Caganova, C. Carrisi, G. Varano, F. Mainoldi, F. Zanardi, P.-L. Germain, L. George, F. Alberghini, L. Ferrarini, A. K. Talukder, M. Ponzoni, G. Testa, T. Nojima, C. Doglioni, D. Kitamura, K.-M. Toellner, I. H. Su, S. Casola, Germinal center dysregulation by histone methyltransferase EZH2 promotes lymphomagenesis. J. Clin. Invest. 123, 5009-5022 (2013).
113. S. He, F. Xie, Y. Liu, Q. Tong, K. Mochizuki, P. E. Lapinski, R.-S. Mani, P. Reddy, I. Mochizuki, A. M. Chinnaiyan, S. Mineishi, P. D. King, Y. Zhang, The histone methyltransferase Ezh2 is a crucial epigenetic regulator of allogeneic T-cell responses mediating graft-versus-host disease. Blood 122, 4119-4128 (2013).
114. M. DuPage, G. Chopra, J. Quiros, W. L. Rosenthal, M. M. Morar, D. Holohan, R. Zhang, L. A. Turka, A. Marson, J. A. Bluestone, The chromatin-modifying enzyme Ezh2 is critical for the maintenance of regulatory t cell identity after activation. Immunity 42, 227-238 (2015).
115. K. A. Newell, A. Asare, A. D. Kirk, T. D. Gisler, K. Bourcier, M. Suthanthiran, W. J. Burlingham, W. H. Marks, I. Sanz, R. I. Lechler, M. P. Hernandez-Fuentes, L. A. Turka, V. L. Seyfert-Margolis; Immune Tolerance Network ST507 Study Group, Identification of a B cell signature associated with renal transplant tolerance in humans. J. Clin. Invest. 120, 1836-1847 (2010).
116. P. Sagoo, E. Perucha, B. Sawitzki, S. Tomiuk, D. A. Stephens, P. Miqueu, S. Chapman, L. Craciun, R. Sergeant, S. Brouard, F. Rovis, E. Jimenez, A. Ballow, M. Giral, I. Rebollo-Mesa, A. Le Moine, C. Braudeau, R. Hilton, B. Gerstmayer, K. Bourcier, A. Sharif, M. Krajewska, G. M. Lord, I. Roberts, M. Goldman, K. J. Wood, K. Newell, V. Seyfert-Margolis, A. N. Warrens, U. Janssen, H.-D. Volk, J.-P. Soulillou, M. P. Hernandez-Fuentes, R. I. Lechler, Development of a cross-platform biomarker signature to detect renal transplant tolerance in humans. J. Clin. Invest. 120, 1848-1861 (2010).
117. M. C. Londoño, R. Danger, M. Giral, J. P. Soulillou, A. Sánchez-Fueyo, S. Brouard, A need for biomarkers of operational tolerance in liver and kidney transplantation. Am. J. Transplant. 12, 1370-1377 (2012).
118. H. Morris, S. DeWolf, H. Robins, B. Sprangers, S. A. LoCascio, B. A. Shonts, T. Kawai, W. Wong, S. Yang, J. Zuber, Y. Shen, M. Sykes, Tracking donor-reactive T cells: Evidence for clonal deletion in tolerant kidney transplant patients. Sci. Transl. Med. 7, 272ra10 (2015).
119. J. E. Levine, B. R. Logan, J. Wu, A. M. Alousi, J. Bolaños-Meade, J. L. M. Ferrara, V. T. Ho, D. J. Weisdorf, S. Paczesny, Acute graft-versus-host disease biomarkers measured during therapy can predict treatment outcomes: A blood and marrow transplant clinical trials network study. Blood 119, 3854-3860 (2012).
120. M. T. Vander Lugt, T. M. Braun, S. Hanash, J. Ritz, V. T. Ho, J. H. Antin, Q. Zhang, C.-H. Wong, H. Wang, A. Chin, A. Gomez, A. C. Harris, J. E. Levine, S. W. Choi, D. Couriel, P. Reddy, J. L. M. Ferrara, S. Paczesny, ST2 as a marker for risk of therapy-resistant graft-versus-host disease and death. N. Engl. J. Med. 369, 529-539 (2013).
121. C. L. Kitko, J. E. Levine, B. E. Storer, X. Chai, D. A. Fox, T. M. Braun, D. R. Couriel, P. J. Martin, M. E. Flowers, J. A. Hansen, L. Chang, M. Conlon, B. J. Fiema, R. Morgan, P. Pongtornpipat, K. Lamiman, J. L. M. Ferrara, S. J. Lee, S. Paczesny, Plasma CXCL9 elevations correlate with chronic GVHD diagnosis. Blood 123, 786-793 (2014).
122. J. E. Levine, T. M. Braun, A. C. Harris, E. Holler, A. Taylor, H. Miller, J. Magenau, D. J. Weisdorf, V. T. Ho, J. Bolaños-Meade, A. M. Alousi, J. L. M. Ferrara; Blood and Marrow Transplant Clinical Trials Network, A prognostic score for acute graft-versus-host disease based on biomarkers: A multicentre study. Lancet Haematol. 2, e21-e29 (2015).