Manipulating the immune system for anti-tumor responses and transplant tolerance via mixed hematopoietic chimerism

Immunological Reviews

Volumn 223, Issue 1, 2008, Pages 334-360

  Gibbons, Carrie ^a   Sykes, Megan ^a  

^a MASSACHUSETTS GENERAL HOSPITAL   (United States)

Author keywords

Graft versus host disease; Graft versus tumor; Hematopoietic cell transplantation; Mixed chimerism; Tolerance

Indexed keywords

CYTOKINE; HLA ANTIGEN;

AUTOIMMUNE DISEASE; B LYMPHOCYTE; BONE MARROW TRANSPLANTATION; CD4+ T LYMPHOCYTE; CD8+ T LYMPHOCYTE; CHIMERA; CYTOKINE PRODUCTION; CYTOTOXIC T LYMPHOCYTE; GRAFT VERSUS HOST REACTION; GRAFT VERSUS LEUKEMIA EFFECT; HEMATOLOGIC MALIGNANCY; HEMATOPOIETIC STEM CELL TRANSPLANTATION; HLA TYPING; HUMAN; IMMUNOLOGICAL TOLERANCE; IMMUNOSUPPRESSIVE TREATMENT; INFECTION; KIDNEY TRANSPLANTATION; MIXED CHIMERISM; NATURAL KILLER CELL; NONHUMAN; PRIORITY JOURNAL; REVIEW; TRANSPLANTATION TOLERANCE; TUMOR IMMUNITY; WHOLE BODY RADIATION;

ANIMALS; CHIMERISM; GRAFT VS HOST DISEASE; GRAFT VS TUMOR EFFECT; HEMATOLOGIC NEOPLASMS; HEMATOPOIETIC STEM CELL TRANSPLANTATION; HISTOCOMPATIBILITY; HLA ANTIGENS; HUMANS; IMMUNITY, CELLULAR; MICE; TRANSPLANTATION CONDITIONING; TRANSPLANTATION TOLERANCE;

EID: 47249105575     PISSN: 01052896     EISSN: 1600065X     Source Type: Journal    
DOI: 10.1111/j.1600-065X.2008.00636.x     Document Type: Review

References (275)

1. Mimeault M, Hauke R, Batra SK. Stem cells: a revolution in therapeutics-recent advances in stem cell biology and their therapeutic applications in regenerative medicine and cancer therapies. Clin Pharmacol Ther 2007 82 : 252 264.
2. Behfar A, Terzic A. Cardioprotective repair through stem cell-based cardiopoiesis. J Appl Physiol 2007 103 : 1438 1440.
3. Le Blanc K, Tammik C, Rosendahl K, Zetterberg E, Ringden O. HLA expression and immunologic properties of differentiated and undifferentiated mesenchymal stem cells. Exp Hematol 2003 31 : 890 896.
4. Aggarwal S, Pittenger MF. Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood 2005 105 : 1815 1822.
5. Klyushnenkova E, et al. T cell responses to allogeneic human mesenchymal stem cells: immunogenicity, tolerance, and suppression. J Biomed Sci 2005 12 : 47 57.
6. Zappia E, et al. Mesenchymal stem cells ameliorate experimental autoimmune encephalomyelitis inducing T-cell anergy. Blood 2005 106 : 1755 1761.
7. Le Blanc K, Ringden O. Mesenchymal stem cells: properties and role in clinical bone marrow transplantation. Curr Opin Immunol 2006 18 : 586 591.
8. Le Blanc K, Ringden O. Immunobiology of human mesenchymal stem cells and future use in hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2005 11 : 321 334.
9. Fibbe WE, Nauta AJ, Roelofs H. Modulation of immune responses by mesenchymal stem cells. Ann NY Acad Sci 2007 1106 : 272 278.
10. Le Blanc K, et al. Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells. Lancet 2004 363 : 1439 1441.
11. Ohnishi S, Ohgushi H, Kitamura S, Nagaya N. Mesenchymal stem cells for the treatment of heart failure. Int J Hematol 2007 86 : 17 21.
12. Hsu YC, Lee DC, Chiu IM. Neural stem cells, neural progenitors, and neurotrophic factors. Cell Transplant 2007 16 : 133 150.
13. Okita K, Ichisaka T, Yamanaka S. Generation of germline-competent induced pluripotent stem cells. Nature 2007 448 : 313 317.
14. Takahashi K, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 2007 131 : 861 872.
15. Fairchild PJ, Cartland S, Nolan KF, Waldmann H. Embryonic stem cells and the challenge of transplantation tolerance. Trends Immunol 2004 25 : 465 470.
16. Lorenz E, Uphoff D, Reid TR, Shelton E. Modification of irradiation injury in mice and guinea pigs by bone marrow injections. J Natl Cancer Inst 1951 12 : 197 201.
17. Jacobson LO, Marks EK. The role of the spleen in radiation injury. Proc Soc Exp Biol Med 1949 70 : 740 742.
18. Storb R. Allogeneic hematopoietic stem cell transplantation - yesterday, today, and tomorrow. Exp Hematol 2003 31 : 1 10.
19. Petersdorf E, et al. Genomics of unrelated-donor hematopoietic cell transplantation. Curr Opin Immunol 2001 13 : 582 589.
20. Fefer A. Graft-versus-tumor responses. In : Thomas ED, Blume KG, Forman SJ, Eds. Hematopoietic Cell Transplantation, Malden, MA : Blackwell Science, 1999 : 316 326.
21. Martin PJ, et al. Graft failure in patients receiving T cell-depleted HLA-identical allogeneic marrow transplants. Bone Marrow Transplant 1988 3 : 445 456.
22. Aversa F, et al. Treatment of high-risk acute leukemia with T cell-depleted stem cells from related donors with one fully mismatched haplotype. New Engl J Med 1998 339 : 1186 1193.
23. Lan F, Zeng D, Higuchi M, Huie P, Higgins JP, Strober S. Predominance of NK1.1(+)TCRalphabeta(+) or DX5(+)TCRalphabeta(+) T Cells in mice conditioned with fractionated lymphoid irradiation protects against graft-versus-host disease: "natural suppressor" cells. J Immunol 2001 167 : 2087 2096.
24. Pillai AB, George TI, Dutt S, Teo P, Strober S. Host NKT cells can prevent graft-versus-host disease and permit graft antitumor activity after bone marrow transplantation. J Immunol 2007 178 : 6242 6251.
25. Edinger M, et al. CD4(+)CD25(+) regulatory T cells preserve graft-versus-tumor activity while inhibiting graft-versus-host disease after bone marrow transplantation. Nat Med 2003 9 : 1144 1150.
26. Nguyen VH, et al. The impact of regulatory T cells on T cell immunity following hematopoeitic cell transplantation. Blood 2008 111 : 945 953.
27. Fowler DH, Breglio J, Nagel G, Eckhaus MA, Gress RE. Allospecific CD8+ Tc1 and Tc2 populations in graft-versus-leukemia effect and graft-versus-host disease. J Immunol 1996 157 : 4811 4821.
28. Fowler DH, et al. Phase I clinical trial of costimulated, IL-4 polarized donor CD4+ T cells as augmentation of allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant 2006 12 : 1150 1160.
29. Lowsky R, et al. Protective conditioning for acute graft-versus-host disease. N Engl J Med 2005 353 : 1321 1331.
30. Ruggeri L, et al. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science 2002 295 : 2097 2100.
31. Sykes M, Romick ML, Hoyles KA, Sachs DH. In vivo administration of interleukin 2 plus T cell-depleted syngeneic marrow prevents graft-versus-host disease mortality and permits alloengraftment. J Exp Med 1990 171 : 645 658.
32. Brok HPM, Heidt PJ, Van der Meide PH, Zurcher C, Vossen JM. Interferon-gamma prevents graft-versus-host disease after allogeneic bone marrow transplantation in mice. J Immunol 1993 151 : 6451 6459.
33. Sykes M, Szot GL, Nguyen PL, Pearson DA. Interleukin-12 inhibits murine graft-vs-host disease. Blood 1995 86 : 2429 2438.
34. Hill GR, et al. Interleukin-11 promotes T cell polarization and prevents acute graft- versus-host disease after allogeneic bone marrow transplantation. J Clin Invest 1998 102 : 115 123.
35. Sykes M, Romick ML, Sachs DH. Interleukin 2 prevents graft-vs-host disease while preserving the graft-vs-leukemia effect of allogeneic T cells. Proc Natl Acad Sci USA 1990 87 : 5633 5637.
36. Sykes M, Harty MW, Szot GL, Pearson DA. Interleukin-2 inhibits graft-versus-host disease-promoting activity of CD4+ cells while preserving CD4- and CD8-mediated graft-versus-leukemia effects. Blood 1994 83 : 2560 2569.
37. Yang Y-G, Sergio JJ, Pearson DA, Szot GL, Shimizu A, Sykes M. Interleukin-12 preserves the graft-versus-leukemia effect of allogeneic CD8 T cells while inhibiting CD4-dependent graft-vs-host disease in mice. Blood 1997 90 : 4651 4660.
38. Teshima T, et al. IL-11 separates graft-versus-leukemia effects from graft-versus-host disease after bone marrow transplantation. J Clin Invest 1999 104 : 317 325.
39. Reddy P, et al. Pretreatment of donors with interleukin-18 attenuates acute graft-versus-host disease via STAT6 and preserves graft-versus-leukemia effects. Blood 2003 101 : 2877 2885.
40. Yang Y-G, Dey B, Sergio JJ, Pearson DA, Sykes M. Donor-derived Interferon γ is required for inhibition of acute GVHD by interleukin 12. J Clin Invest 1998 102 : 2126 2135.
41. Yang Y-G, Qi J, Wang M-G, Sykes M. Donor-derived interferon g separates graft-versus-leukemia effects and graft-versus-host disease induced by donor CD8 T cells. Blood 2002 99 : 4207 4215.
42. Asavaroengchai W, Wang S, Wang H, Wang L, Bronson R, Sykes M, Yang Y-G. An essential role for IFN-gamma in regulation of alloreactive CD8 T cells following allogeneic hematpoietic cell tranplantation. Biol Blood Marrow Transplant 2007 13 : 46 55.
43. Sawitzki B, Kingsley CI, Oliveira V, Karim M, Herber M, Wood KJ. IFN-{gamma} production by alloantigen-reactive regulatory T cells is important for their regulatory function in vivo. J Exp Med 2005 201 : 1925 1935.
44. Wang M-G, Szebeni J, Pearson DA, Szot GL, Sykes M. Inhibition of graft-vs-host disease (GVHD) by IL-2 treatment is associated with altered cytokine production by expanded GVH-reactive CD4+ helper cells. Transplantation 1995 60 : 481 490.
45. Zorn E, et al. IL-2 regulates FOXP3 expression in human CD4+CD25+ regulatory T cells through a STAT-dependent mechanism and induces the expansion of these cells in vivo. Blood 2006 108 : 1571 1579.
46. Ahmadzadeh M, Rosenberg SA. IL-2 administration increases CD4+CD25(hi) Foxp3+ regulatory T cells in cancer patients. Blood 2006 107 : 2409 2414.
47. Graubert TA, DiPersio JF, Russell JH, Ley TJ. Perforin/granzyme-dependent and independent mechanisms are both important for the development of graft-versus-host disease after murine bone marrow transplantation. J Clin Invest 1997 100 : 904 911.
48. Schmaltz C, et al. Differential use of Fas ligand and perforin cytotoxic pathways by donor T cells in graft-versus-host disease and graft-versus-leukemia effect. Blood 2001 97 : 2886 2895.
49. Schmaltz C, et al. T cells require TRAIL for optimal graft-versus-tumor activity. Nat Med 2002 8 : 1433 1437.
50. Marks L, Altman NH, Podack ER, Levy RB. Donor T cells lacking Fas ligand and perforin retain the capacity to induce severe GvHD in minor histocompatibility antigen mismatched bone-marrow transplantation recipients. Transplantation 2004 77 : 804 812.
51. Murphy WJ, Blazar BR. New strategies for preventing graft-versus-host disease. Curr Opin Immunol 1999 11 : 509 515.
52. Kim Y-M, Sachs T, Asavaroengchai W, Bronson R, Sykes M. Graft-versus-host disease (GvHD) can be separated from graft-versus-lymphoma effects by controlling lymphocyte trafficking with FTY720. J Clin Invest 2003 111 : 659 669.
53. Liao JJ, Huang MC, Goetzl EJ. Cutting edge: alternative signaling of Th17 cell development by sphingosine 1-phosphate. J Immunol 2007 178 : 5425 5428.
54. Taylor PA, et al. Insights into the mechanism of FTY720 and compatibility with regulatory T cells for the inhibition of graft-versus-host disease (GVHD). Blood 2007 110 : 3480 3488.
55. Mapara M, Kim Y, Marx J, Sykes M. Donor lymphocyte infusion-mediated graft-versus-leukemia effects in mixed chimeras established with a nonmyeloablative conditioning regimen: extinction of graft-versus-leukemia effects after coversion to full donor chimerism. Transplantation 2003 76 : 297 305.
56. Mapara MY, Kim Y-M, Wang S-P, Bronson R, Sachs DH, Sykes M. Donor lymphocyte infusions mediate superior graft-versus-leukemia effects in mixed compared to fully allogeneic chimeras: a critical role for host antigen-presenting cells. Blood 2002 100 : 1903 1909.
57. Sykes M, Sheard MA, Sachs DH. Graft-versus-host-related immunosuppression is induced in mixed chimeras by alloresponses against either host or donor lymphohematopoietic cells. J Exp Med 1988 168 : 2391 2396.
58. Pelot MR, et al. Lymphohematopoietic graft-vs-host reactions can be induced without graft-vs-host disease in murine mixed chimeras established with a cyclophosphamide-based non-myeloablative conditioning regimen. Biol Blood Marrow Transplant 1999 5 : 133 143.
59. Chakraverty R, et al. Host MHC class II+ antigen-presenting cells and CD4 cells are required for CD8-mediated graft-versus-leukemia responses following delayed donor leukocyte infusions. Blood 2006 108 : 2106 2113.
60. Chakraverty R, et al. An inflammatory checkpoint regulates recruitment of graft-versus-host-reactive T cells to peripheral tissues. J Exp Med 2006 203 : 2021 2031.
61. Mapara MY, et al. Expression of chemokines in GVHD target organs is influenced by conditioning and genetic factors and amplified by GVHR. Biol Blood Marrow Transplant 2006 12 : 623 634.
62. Kolb H, Holler E. Adoptive immunotherapy with donor lymphocyte transfusions. Curr Opin Oncol 1997 9 : 139 145.
63. Antin JH. Graft-versus-leukemia: no longer an epiphenomenon. Blood 1993 82 : 2273 2277.
64. Spitzer TR, et al. Non-myeloablative haploidentical stem cell transplantation using anti-CD2 monoclonal antibody (MEDI-507)-based conditioning for refractory hematologic malignancies. Transplantation 2003 75 : 1748 1751.
65. Johnson BD, Becker EE, LaBelle JL, Truitt RL. Role of immunoregulatory donor T cells in suppression of graft-versus-host disease following donor leukocyte infusion therapy. J Immunol 1999 163 : 6479 6487.
66. Blazar BR, et al. Host T cells resist graft-versus-host disease mediated by donor leukocyte infusions. J Immunol 2000 165 : 4901 4909.
67. Johnson BD, Becker EE, Truitt RL. Graft-vs.-host and graft-vs.-leukemia reactions after delayed infusions of donor T-subsets. Biol Blood Marrow Transplant 1999 5 : 123 132.
68. Johnson BD, Konkol MC, Truitt RL. CD25+ immunoregulatory T-cells of donor origin suppress alloreactivity after BMT. Biol Blood Marrow Transplant 2002 8 : 525 535.
69. Bonini C, et al. HSV-TK gene transfer into donor lymphocytes for control of allogeneic graft-versus-leukemia. Science 1997 276 : 1719 1724.
70. Contassot E, et al. Ganciclovir-sensitive acute graft-versus-host disease in mice receiving herpes simplex virus-thymidine kinase-expressing donor T cells in a bone marrow transplantation setting. Transplantation 2000 69 : 503 508.
71. Falkenburg JHF, et al. Complete remission of accelerated phase chronic myeloid leukemia by tratment with leukemia-reactive cytotoxic T lymphocytes. Blood 1999 94 : 1201 1208.
72. Kwak LW, Pennington R, Longo DL. Active immunization of murine allogeneic bone marrow transplant donors with B-cell tumor-derived idiotype: a strategy for enhancing the specific antitumor effect of marrow grafts. Blood 1996 87 : 3053 3060.
73. Bendani M, et al. Complete molecular remissions induced by patient-specific vaccination plus granulocyte-monocyte colony-stimulating factor against lymphoma. Nat Med 1999 5 : 1171 1177.
74. Mutis T, Verdijk R, Schrama E, Esendam B, Brand A, Goulmy E. Feasibility of immunotherapy of relapsed leukemia with ex vivo-generated cytotoxic T lymphocytes specific for hematopoietic system-restricted minor histocompatibility antigens [see comments]. Blood 1999 93 : 2336 2341.
75. Fontaine P, Roy-Proulx G, Knafo L, Baron C, Roy DC, Perreault C. Adoptive transfer of minor histocompatibility antigen-specific T lymphocytes eradicates leukemia cells without causing graft-versus-host disease. Nat Med 2001 7 : 789 794.
76. Chen L. Immunological ignorance of silent antigens as an explanation of tumor evasion. Immunol Today 1998 19 : 27 29.
77. Dudley ME, et al. Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science 2002 298 : 850 854.
78. Spitzer TR, et al. The intentional induction of mixed chimerism and achievement of anti-tumor responses following non-myeloablative conditioning therapy and HLA-matched and mismatched donor bone marrow transplantation for refractory hematologic malignancies. Biol Blood Marrow Transplant 2000 6 : 309 320.
79. Kraus AB, et al. Early host CD8 T-cell recovery and sensitized anti-donor IL-2-producing and cytolytic T-cell responses associated with marrow graft rejection following nonmyeloablative bone marrow transplantation. Exp Hematol 2003 31 : 609 621.
80. Rubio MT, Kim YM, Sachs T, Mapara M, Zhao G, Sykes M. Anti-tumor effect of donor marrow graft rejection induced by recipient leukocyte infusions in mixed chimeras prepared with nonmyeloablative conditioning: critical role for recipient-derived IFN-{gamma}. Blood 2003 102 : 2300 2307.
81. Saito TI, Rubio MT, Sykes M. Clinical relevance of recipient leukocyte infusion as antitumor therapy following nonmyeloablative allogeneic hematopoietic cell transplantation. Exp Hematol 2006 34 : 1271 1277.
82. Rubio MT, Saito TI, Kattelman K, Zhao G, Buchli J, Sykes M. Mechanisms of the anti-tumor responses and host-versus graft reactions induced by recipient leukocyte infusions in mixed chimeras prepared with nonmyeloablative conditioning: a critical role for recipient CD4+ T cells and recipient leukocyte infusion-derived IFN-gamma-producing CD8+ T cells. J Immunol 2005 175 : 665 676.
83. Rubio MT, Zhao G, Buchli J, Chittenden M, Sykes M. Role of indirect allo- and autoreactivity in anti-tumor responses induced by recipient leukocyte infusions (RLI) in mixed chimeras prepared with nonmyeloablative conditioning. Clin Immunol 2006 120 : 33 44.
84. Afzali B, Lechler RI, Hernandez-Fuentes MP. Allorecognition and the alloresponse: clinical implications. Tissue Antigens 2007 69 : 545 556.
85. Chen D, Weber M, Lechler R, Dorling A. NK-cell-dependent acute xenograft rejection in the mouse heart-to-rat model. Xenotransplantation 2006 13 : 408 414.
86. Kitchens WH, Uehara S, Chase CM, COLVIN RB, Russell PS, Madsen JC. The changing role of natural killer cells in solid organ rejection and tolerance. Transplantation 2006 81 : 811 817.
87. McNerney ME, et al. Role of natural killer cell subsets in cardiac allograft rejection. Am J Transplant 2006 6 : 505 513.
88. Maier S, et al. Inhibition of natural killer cells results in acceptance of cardiac allografts in CD28-/- mice. Nat Med 2001 7 : 557 562.
89. Kean LS, et al. NK cells mediate costimulation blockade-resistant rejection of allogeneic stem cells during nonmyeloablative transplantation. Am J Transplant 2006 6 : 292 304.
90. Chen L, et al. TLR engagement prevents transplantation tolerance. Am J Transplant 2006 6 : 2282 2291.
91. Obhrai J, Goldstein DR. The role of toll-like receptors in solid organ transplantation. Transplantation 2006 81 : 497 502.
92. Streblow DN, Orloff SL, Nelson JA. Acceleration of allograft failure by cytomegalovirus. Curr Opin Immunol 2007 19 : 577 582.
93. Thornley TB, et al. TLR agonists abrogate costimulation blockade-induced prolongation of skin allografts. J Immunol 2006 176 : 1561 1570.
94. Knoechel B, et al. Functional and molecular comparison of anergic and regulatory T lymphocytes. J Immunol 2006 176 : 6473 6483.
95. Rocken M, Urban JF, Shevach EM. Infection breaks T-cell tolerance. Nature 1992 359 : 79 82.
96. Tomita Y, Khan A, Sykes M. Role of intrathymic clonal deletion and peripheral anergy in transplantation tolerance induced by bone marrow transplantion in mice conditioned with a non-myeloablative regimen. J Immunol 1994 153 : 1087 1098.
97. Sharabi Y, Sachs DH. Mixed chimerism and permanent specific transplantation tolerance induced by a non-lethal preparative regimen. J Exp Med 1989 169 : 493 502.
98. Tomita Y, Khan A, Sykes M. Mechanism by which additional monoclonal antibody injections overcome the requirement for thymic irradiation to achieve mixed chimerism in mice receiving bone marrow transplantation after conditioning with anti-T cell mAbs and 3 Gy whole body irradiation. Transplantation 1996 61 : 477 485.
99. Tomita Y, Sachs DH, Khan A, Sykes M. Additional mAb injections can replace thymic irradiation to allow induction of mixed chimerism and tolerance in mice receiving bone marrow transplantation after conditioning with anti-T cell mAbs and 3 Gy whole body irradiation. Transplantation 1996 61 : 469 477.
100. Nikolic B, Khan A, Sykes M. Induction of tolerance by mixed chimerism with nonmyeloblative host conditioning: the importance of overcoming intrathymic alloresistance. Biol Blood Marrow Transplant 2001 7 : 144 153.
101. Owen RD. Immunogenetic consequences of vascular anastomoses between bovine twins. Science 1945 102 : 400 401.
102. Anderson D, Billingham RE, Lampkin GH, Medawar PB. The use of skin grafting to distinguish between monozygotic and dizygotic twins in cattle. Heredity 1951 5 : 379 397.
103. Billingham RE, Lampkin GH, Medawar PB, Williams HLI. Tolerance to homografts, twin diagnosis, and the freemartin condition in cattle. Heredity 1952 6 : 201 212.
104. Billingham RE, Brent L, Medawar PB. "Actively acquired tolerance" of foreign cells. Nature 1953 172 : 603 606.
105. Billingham RE, Brent L, Medawar PB. Acquired tolerance of skin homografts. Ann NY Acad Sci 1955 59 : 409 416.
106. Slavin S, Strober S, Fuks Z, Kaplan HS. Long-term survival of skin allografts in mice treated with fractionated total lymphoid irradiation. Science 1976 193 : 1252 1254.
107. Slavin S, Fuks Z, Kaplan HS, Strober S. Transplantation of allogeneic bone marrow without graft-versus-host disease using total lymphoid irradiation. J Exp Med 1978 147 : 963 972.
108. Ildstad ST, Sachs DH. Reconstitution with syngeneic plus allogeneic or xenogeneic bone marrow leads to specific acceptance of allografts or xenografts. Nature 1984 307 : 168 170.
109. Ildstad ST, Wren SM, Bluestone JA, Barbieri SA, Sachs DH. Characterization of mixed allogeneic chimeras. Immunocompetence, in vitro reactivity, and genetic specificity of tolerance. J Exp Med 1985 162 : 231 244.
110. Cobbold SP, Martin G, Qin S, Waldmann H. Monoclonal antibodies to promote marrow engraftment and tissue graft tolerance. Nature 1986 323 : 164 166.
111. Lenshow DJ, et al. Long-term survival of xenogeneic pancreatic islets induced by CTLA4Ig. Science 1992 257 : 789 792.
112. Linsley PS, et al. Immunosuppression in vivo by a soluble form of the CTLA-4 T cell activation molecule. Science 1992 257 : 792 795.
113. Markees TG, et al. Prolonged survival of mouse skin allografts in recipients treated with donor splenocytes and antibody to CD40 ligand. Transplantation 1997 64 : 329 335.
114. Pearson TC, Alexander DZ, Winn KJ, Linsley PS, Lowry RP, Larsen CP. Transplantation tolerance induced by CTLA4Ig. Transplantation 1994 57 : 1701 1706.
115. Wekerle T, et al. Extrathymic T cell deletion and allogeneic stem cell engraftment induced with costimulatory blockade is followed by central T cell tolerance. J Exp Med 1998 187 : 2037 2044.
116. Wekerle T, Sayegh MH, Chandraker A, Swenson KG, Zhao Y, Sykes M. Role of peripheral clonal deletion in tolerance induction with bone marrow transplantation and costimulatory blockade. Transplant Proc 1999 31 : 680.
117. Wekerle T, et al. Anti-CD154 or CTLA4Ig obviates the need for thymic irradiation in a non-myeloablative conditioning regimen for the induction of mixed hematopoietic chimerism and tolerance. Transplantation 1999 68 : 1348 1355.
118. Ito H, Kurtz J, Shaffer J, Sykes M. CD4 T cell-mediated alloresistance to fully MHC-mismatched allogeneic bone marrow engraftment is dependent on CD40-CD40L interactions, and lasting T cell tolerance is induced by bone marrow transplantation with initial blockade of this pathway. J Immunol 2001 166 : 2981.
119. Sharabi Y, Sachs DH, Sykes M. T cell subsets resisting induction of mixed chimerism across various histocompatibility barriers. Progress Immunol 1992 VIII : 801 805.
120. Takeuchi Y, Ito H, Kurtz J, Wekerle T, Ho L, Sykes M. Earlier low-dose TBI or DST overcomes CD8+ T-cell-mediated alloresistance to allogeneic marrow in recipients of anti-CD40L. Am J Transplant 2004 4 : 31 40.
121. Seung E, et al. Allogeneic hematopoietic chimerism in mice treated with sublethal myeloablation and anti-CD154 antibody: absence of graft-versus-host disease, induction of skin allograft tolerance, and prevention of recurrent autoimmunity in islet-allografted NOD/Lt mice. Blood 2000 95 : 2175 2182.
122. Taylor PA, Lees CJ, Waldmann H, Noelle RJ, Blazar BR. Requirements for the promotion of allogeneic engraftment by anti-CD154 (anti-CD40L) monoclonal antibody under nonmyeloablative conditions. Blood 2001 98 : 467 474.
123. Seung E, Mordes JP, Rossini AA, Greiner DL. Hematopoietic chimerism and central tolerance created by peripheral-tolerance induction without myeloablative conditioning. J Clin Invest 2003 112 : 795 808.
124. Tomita Y, Sachs DH, Sykes M. Myelosuppressive conditioning is required to achieve engraftment of pluripotent stem cells contained in moderate doses of syngeneic bone marrow. Blood 1994 83 : 939 948.
125. Ito H, Takeuchi Y, Shaffer J, Sykes M. Local irradiation enhances congenic donor pluripotent hematopoietic stem cell engraftment similarly in irradiated and non-irradiated sites. Blood 2003 103 : 1949 1954.
126. Stewart FM, Crittenden RB, Lowry PA, Pearson-White S, Quesenberry PJ. Long-term engraftment of normal and post-5-fluorouracil murine marrow into normal nonmyeloablated mice. Blood 1993 81 : 2566 2571.
127. Ramshaw HS, Rao SS, Crittenden RB, Peters SO, Weier H-U, Quesenberry PJ. Engraftment of bone marrow cells into normal unprepared hosts: effects of 5-fluorouracil and cell cycle status. Blood 1995 86 : 924 929.
128. Ramshaw HS, Crittenden RB, Dooner M, Peters SO, Rao SS, Quesenberry PJ. High levels of engraftment with a single infusion of bone marrow cells into normal unprepared mice. Biol Blood Marrow Transplant 1995 1 : 74 80.
129. Rao SS, Peters SO, Crittenden RB., Stewart FM, Ramshaw HS, Quesenberry PJ. Stem cell transplantation in the normal nonmyeloablated host: relationship between cell dose, schedule, and engraftment. Exp Hematol 1997 25 : 114 121.
130. Sykes M, Szot GL, Swenson K, Pearson DA, Wekerle T. Separate regulation of peripheral hematopoietic and thymic engraftment. Exp Hematol 1998 26 : 457 465.
131. Sykes M, Szot GL, Swenson K, Pearson DA. Induction of high levels of allogeneic hematopoietic reconstitution and donor-specific tolerance without myelosuppressive conditioning. Nat Med 1997 3 : 783 787.
132. Wekerle T, et al. Allogeneic bone marrow translantation with costimulatory blockade induces macrochimerism and tolerance without cytoreductive host treatment. Nat Med 2000 6 : 464 469.
133. Durham MM, et al. Cutting edge: administration of anti-CD40 ligand and donor bone marrow leads to hemopoietic chimerism and donor-specific tolerance without cytoreductive conditioning. J Immunol 2000 165 : 1 4.
134. Domenig C, et al. Roles of deletion and regulation in creating mixed chimerism and allograft tolerance using a nonlymphoablative irradiation-free protocol. J Immunol 2005 175 : 51 60.
135. Joffre O, Santolaria T, Calise D, Al Saati T, Hudrisier D, Romangnoli P, Van Meerwij KJ. Prevention of acute and chronic allograft rejection with CD4+CD25+Foxp3+ regulatory T lymphocytes. Nat Med 2008 14 : 88 92.
136. Huang CA, Fuchimoto Y, Sheir-Dolberg R, Murphy MC, Neville DM Jr., Sachs DH. Stable mixed chimerism and tolerance using a non-myeloablative preparative regimen in a large animal model. J Clin Invest 2000 105 : 173 181.
137. Schwarze ML, et al. Mixed hematopoietic chimerism induces long term tolerance to cardiac allografts in miniature swine. Ann Thorac Surg 2000 70 : 131 138.
138. Cina RA, et al. Stable multilineage chimerism without graft versus host disease following nonmyeloablative haploidentical hematopoietic cell transplantation. Transplantation 2006 81 : 1677 1685.
139. Gleit ZL, et al. Variable relationship between chimerism and tolerance after hematopoietic cell transplantation without myelosuppressive conditioning. Transplantation 2002 74 : 1535 1544.
140. Horner BM, et al. Predictors of organ allograft tolerance following hematopoietic cell transplantation. Am J Transplant 2006 6 : 2894 2902.
141. Storb R, et al. Stable mixed hematopietic chimerism in DLA-identical littermate dogs given sublethal total body irradiation before and pharmacological immunosuppression after marrow transplantation. Blood 1997 89 : 3048 3054.
142. Kuhr CS, et al. Tolerance to vascularized kidney grafts in canine mixed hematopoietic chimeras. Transplantation 2002 73 : 1487 1492.
143. Storb R, et al. Stable mixed hmeatopoietic chimerism in dogs given donor antigen, CTLA4Ig, and 100 cGy total body irradiation before and pharmacologic immunosuppression after marrow transplant. Blood 1999 94 : 2523 2529.
144. Kawai T, et al. Mixed allogeneic chimerism and renal allograft tolerance in cynomologous monkeys. Transplantation 1995 59 : 256 262.
145. Kawai T, et al. Effect of mixed hematopoietic chimerism on cardiac allograft survival in cynomolgus monkeys. Transplantation 2002 73 : 1757 1764.
146. Boskovic S, et al. Monitoring antidonor alloantibodies as a predictive assay for renal allograft tolerance/long-term observations in nonhuman primates. Transplantation 2006 82 : 819 825.
147. Aksentijevich I, Sachs DH, Sykes M. Natural antibodies can inhibit bone marrow engraftment in the rat - mouse species combination. J. Immunol 1991 147 : 4140 4146.
148. Kawai T, et al. CD154 blockade for induction of mixed chimerism and prolonged renal allograft survival in nonhuman primates. Am J Transplant 2004 4 : 1391 1398.
149. Ildstad ST, Wren SM, Sharrow SO, Stephany D, Sachs DH. In vivo and in vitro characterization of specific hyporeactivity to skin xenografts in mixed xenogeneically reconstituted mice (B10+F344 rat - >B10). J Exp Med 1984 160 : 1820 1835.
150. Sharabi Y, Aksentijevich I, Sundt TM III., Sachs DH, Sykes M. Specific tolerance induction across a xenogeneic barrier: production of mixed rat/mouse lymphohematopoietic chimeras using a nonlethal preparative regimen. J Exp Med 1990 172 : 195 202.
151. Nikolic B, Cooke DT, Zhao G, Sykes M. Both g/d T cells and NK cells inhibit the engraftment of xenogeneic rat bone marrow cells in mice. J Immunol 2001 166 : 1398 1404.
152. Lee LA, Sergio JJ, Sykes M. Evidence for non-immune mechanisms in the loss of hematopoietic chimerism in rat-mouse mixed xenogeneic chimeras. Xenotransplant 1995 2 : 57 66.
153. Gritsch HA, Sykes M. Host marrow has a competitive advantage which limits donor hematopietic repopulation in mixed xenogeneic chimeras. Xenotransplant 1996 3 : 312 320.
154. Aksentijevich I, Sachs DH, Sykes M. Humoral tolerance in xenogeneic BMT recipients conditioned with a non-myeloablative regimen. Transplantation 1992 53 : 1108 1114.
155. Kawahara T, Rodriguez-Barbosa JI, Zhao Y, Zhao G, Sykes M. Global unresponsiveness as a mechanism of natural killer cell tolerance in mixed xenogeneic chimeras. Am J Transplant 2007 7 : 2090 2097.
156. Ohdan H, Yang Y-G, Shimizu A, Swenson KG, Sykes M. Mixed bone marrow chimerism induced without lethal conditioning prevents T cell and anti-Gala1,3Gal-mediated graft rejection. J Clin Invest 1999 104 : 281 290.
157. Ohdan H, Swenson KG, Kitamura H, Yang Y-G, Sykes M. Tolerization of Gala1,3Gal-reactive B cells in presensitized a1,3-galactosyltransferase- deficient mice by nonmyeloablative induction of mixed chimerism. Xenotransplantation 2002 8 : 227 238.
158. Yang Y-G, et al. Tolerization of anti-gala1-3gal natural antibody-forming B cells by induction of mixed chimerism. J Exp Med 1998 187 : 1335 1342.
159. Lan P, et al. Induction of human T cell tolerance to porcine xenoantigens through mixed hematopoietic chimerism. Blood 2004 103 : 3964 3969.
160. Abe M, et al. Elimination of porcine hematopoietic cells by macrophages in mice. J Immunol 2002 168 : 621 628.
161. Wang H, et al. Attenuation of phagocytosis of xenogeneic cells by manipulating CD47. Blood 2007 109 : 836 842.
162. Ide K, et al. Role for CD47-SIRPalpha signaling in xenograft rejection by macrophages. Proc Natl Acad Sci USA 2007 104 : 5062 5066.
163. Simon AR, Warrens AN, Yazzie NP, Seebach JD, Sachs DH, Sykes M. Cross-species interaction of porcine and human integrins with their respective ligands. Implications for xenogeneic tolerance induction. Transplantation 1998 66 : 385 394.
164. + cells in mice expressing porcine cytokines: toward tolerance induction across discordant xenogeneic barriers. Transplantation 2000 69 : 2484 2490.
165. Yang Y-G, Sergio JJ, Swenson K, Glaser RM, Monroy R, Sykes M. Donor-specific growth factors promote swine hematopoiesis in SCID mice. Xenotransplant 1996 3 : 92 101.
166. Yang YG, Sykes M. Xenotransplantation: current status and a perspective on the future. Nat Rev Immunol 2007 7 : 519 531.
167. Sharabi Y, Abraham VS, Sykes M, Sachs DH. Mixed allogeneic chimeras prepared by a non-myeloablative regimen: requirement for chimerism to maintain tolerance. Bone Marrow Transplant 1992 9 : 191 197.
168. Khan A, Tomita Y, Sykes M. Thymic dependence of loss of tolerance in mixed allogeneic bone marrow chimeras after depletion of donor antigen. Peripheral mechanisms do not contribute to maintenance of tolerance. Transplantation 1996 62 : 380 387.
169. Ramsdell F, Fowlkes BJ. Maintenance of in vivo tolerance by persistence of antigen. Science 1992 257 : 1130 1134.
170. Rocha B, Tanchot C, Von Boehmer H. Clonal anergy blocks in vivo growth of mature T cells and can be reversed in the absence of antigen. J Exp Med 1993 177 : 1517 1521.
171. Manilay JO, Pearson DA, Sergio JJ, Swenson KG, Sykes M. Intrathymic deletion of alloreactive T cells in mixed bone marrow chimeras prepared with a nonmyeloablative conditioning regimen. Transplantation 1998 66 : 96 102.
172. Kurtz J, Shaffer J, Anosova N, Benichou G, Sykes M. Mechanisms of early peripheral CD4 T cell tolerance induction by anti-CD154 monoclonal antibody and allogeneic bone marrow transplantation: evidence for anergy and deletion, but not regulatory cells. Blood 2004 103 : 4336 4343.
173. Kurtz J, Ito H, Wekerle T, Shaffer J, Sykes M. Mechanisms involved in the establishment of tolerance through costimulatory blockade and BMT: Lack of requirement for CD40L-mediated signaling for tolerance or deletion of donor-reactive CD4+ cells. Am J Transplant 2001 1 : 339 349.
174. Brunner T, et al. Cell-autonomous Fas (CD95)/Fas-ligand interaction mediates activation-induced apoptosis in T-cell hybridomas. Nature 1995 373 : 441 444.
175. Nakamura M, Ogawa N, Shalabi A, Maley WR, Longo D, Burdick JF. Positive effect on T-cell regulatory apoptosis by mycophenolate mofetil. Clin. Transplant 2001 15 (Suppl. 6) : 36 40.
176. Kurtz J, et al. Lack of role for CsA-sensitive or Fas pathways in the tolerization of CD4+ T cells via BMT and anti-CD40L. Am J Transplant 2003 3 : 804 816.
177. Wekerle T, et al. Peripheral deletion after bone marrow transplantation with costimulatory blockade has features of both activation-induced cell death and passive cell death. J Immunol 2001 166 : 2311 2316.
178. Rafaeli Y, Van Parijs L, Alexander SI, Abbas AK. Interferon gamma is required for activation-induced death of T lymphocytes. J Exp Med 2002 196 : 999 1005.
179. Billingham RE, Brent L, Medawar PB. Quantitative studies on tissue transplantation immunity. III. Actively acquired tolerance. Philos Trans R Soc 1955 239 (Ser.B) : 44.
180. Gruchalla RS, Strome PG, Streilein JW. Analysis of neonatally induced tolerance of H-2 alloantigens. III. Ease of abolition of tolerance of class I, but not class II, antigens with infusions of syngeneic, immunocompetent cells. Transplantation 1983 36 : 318 323.
181. Lubaroff DM, Silvers WK. The importance of chimerism in maintaining tolerance of skin allografts in mice. J Immunol 1973 111 : 65 71.
182. Ramseier H. Immunization against abolition of transplantation tolerance. Eur J Immunol 1973 3 : 156 164.
183. Wells AD, Walsh MC, Bluestone JA, Turka LA. Signaling through CD28 and CTLA-4 controls two distinct forms of T cell anergy. J Clin Invest 2001 108 : 895 903.
184. Zheng X-X, et al. CTLA4 signals are required to optimally induce allograft tolerance with combined donor-specific transfusion and anti-CD154 monoclonal antibody treatment. J Immunol 1999 162 : 4983 4990.
185. Fehr T, Takeuchi Y, Kurtz J, Sykes M. Early regulation of CD8 T cell alloreactivity by CD4+CD25- T cells in recipients of anti-CD154 antibody and allogeneic BMT is followed by rapid peripheral deletion of donor-reactive CD8+ T cells, precluding a role for sustained regulation. Eur J Immunol 2005 35 : 2679 2690.
186. Wood KJ, Sakaguchi S. Regulatory lymphocytes: regulatory T cells in transplantation tolerance. Nat Rev Immunol 2003 3 : 199 210.
187. Jiang S, Lechler RI, He XS, Huang JF. Regulatory T cells and transplantation tolerance. Hum Immunol 2006 67 : 765 776.
188. Wilczynski JR, Radwan M, Kalinka J. The characterization and role of regulatory T cells in immune reactions. Front Biosci 2008 13 : 2266 2274.
189. Taguchi O, Takahashi T. Administration of anti-interleukin-2 receptor alpha antibody in vivo induces localized autoimmune disease. Eur J Immunol 1996 26 : 1608 1612.
190. Battaglia M, Roncarolo MG. Induction of transplantation tolerance via regulatory T cells. Inflamm Allergy Drug Targets 2006 5 : 157 165.
191. Bigenzahn S, et al. The role of non-deletional tolerance mechanisms in a murine model of mixed chimerism with costimulation blockade. Am J Transplant 2005 5 : 1237 1247.
192. Malek TR, Bayer AL. Tolerance, not immunity, crucially depends on IL-2. Nat Rev Immunol 2004 4 : 665 674.
193. Yamazaki M, et al. Different mechanisms control peripheral and central tolerance in hematopoietic chimeric mice. Am J Transplant 2007 7 : 1710 1721.
194. Barber DL, et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 2006 439 : 682 687.
195. Day CL, et al. PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature 2006 443 : 350 354.
196. Greenwald RJ, Freeman GJ, Sharpe AH. The B7 family revisited. Annu Rev Immunol 2005 23 : 515 548.
197. + T cells, Interferon-g, and CTLA4. J Clin Invest 1998 101 : 2446 2455.
198. Li Y, Zheng XX, Li XC, Zand MS, Strom TB. Combined costimulation blockade plus rapamycin but not cyclosporine produces permanent engraftment. Transplantation 1998 66 : 1387 1388.
199. Kenyon NS, et al. Long-term survival and function of intrahepatic islet allografts in rhesus monkeys treated with humanized anti-CD154. Proc Natl Acad Sci USA 1999 96 : 8132 8137.
200. Kirk AD, et al. Treatment with humanized monoclonal antibody against CD154 prevents acute renal allograft rejection in nonhuman primates. Nat Med 1999 5 : 686 693.
201. Tramblay J, et al. Asialo GM1+CD8+T cells play a critical role in costimulation blockade-resistant allograft rejection. J Clin Invest 1999 104 : 1715 1722.
202. Li Y, Li XC, Zheng XX, Wells AD, Turka LA, Strom TB. Blocking both signal 1 and signal 2 of T-cell activation prevents apoptosis of alloreactive T cells and induction of peripheral allograft tolerance. Nat Med 1999 5 : 1298 1302.
203. Chandraker A, Russell ME, Glysing-Jensen T, Willett TA, Sayegh MH. T-cell costimulatory blockade in experimental chronic cardiac allograft rejection: effects of cyclosporine and donor antigen. Transplantation 1997 63 : 1053 1058.
204. Larsen CP, et al. Long-term acceptance of skin and cardiac allografts after blocking CD40 and CD28 pathways. Nature 1996 381 : 434 438.
205. Dai Z, Konieczny BT, Baddoura FK, Lakkis FG. Impaired alloantigen-mediated T cell apoptosis and failure to induce long-term allograft survival in IL-2-deficient mice. J Immunol 1998 161 : 1659 1663.
206. Konieczny BT, et al. IFN-g is critical for long-term allograft survival induced by blocking the CD28 and CD40 ligand T cell costimulation pathways. J Immunol 1998 160 : 2059 2064.
207. Graca L, Honey K, Adams E, Cobbold SP, Waldmann H. Cutting edge: anti-CD154 therapeutic antibodies induce infectious transplantation tolerance. J Immunol 2000 165 : 4783 4786.
208. Honey K, Cobbold SP, Waldmann H. CD40 ligand blockade induces CD4+ T cell tolerance and linked suppression. J Immunol 1999 163 : 4805 4810.
209. Ferry H, et al. B-cell tolerance. Transplantation 2006 81 : 308 315.
210. Goodnow CC. Transgenic mice and analysis of B-cell tolerance. Ann Rev Immunol 1992 10 : 489 518.
211. Li Y, Ma L, Shen J, Chong AS. Peripheral deletion of mature alloreactive B cells induced by costimulation blockade. Proc Natl Acad Sci USA 2007 104 : 12093 12098.
212. Ohdan H, et al. Mac-1-negative B-1b phenotype of natural antibody-producing cells, including those responding to Gala1,3Gal epitopes in a1,3-galactosyltransferase deficient mice. J Immunol 2000 165 : 5518 5529.
213. Kawahara T, Shimizu I, Ohdan H, Zhao G, Sykes M. Differing mechanisms of early and late B cell tolerance induced by mixed chimerism. Am J Transplant 2005 5 : 2821 2829.
214. Shimizu I, Kawahara T, Haspot F, Bardwell PD, Carroll MC, Sykes M. B-cell extrinsic CR1/CR2 promotes natural antibody production and tolerance induction of anti-alpha-Gal-producing B-1 cells. Blood 2006 109 : 1773 1781.
215. Lee LA, Sergio JJ, Sykes M. Natural killer cells weakly resist engraftment of allogeneic long-term multilineage-repopulating hematopoietic stem cells. Transplantation 1996 61 : 125 132.
216. Zhao Y, Ohdan H, Manilay JO, Sykes M. NK cell tolerance in mixed allogeneic chimeras. J Immunol 2003 170 : 5398 5405.
217. Manilay JO, Waneck GL, Sykes M. Altered expression of Ly-49 receptors on natural killer cells developing in mixed allogeneic bone marrow chimeras. Int Immunol 1998 10 : 1943 1955.
218. Cooke DT, Nikolic B, Sykes M. The role of atypical T cells and NK cells in inhibiting primary engraftment of xenogeneic donor rat bone marrow cells. Transplant Proc 1999 31 : 683.
219. Kim S, et al. Licensing of natural killer cells by host major histocompatibility complex class I molecules. Nature 2005 436 : 709 713.
220. Sasaki H, Xu X-C, Smith DM, Howard T, Mohanakumar T. HLA-G expression protects porcine endothelial cells against natural killer cell-mediated xenogeneic cytotoxicity. Transplantation 1999 67 : 31 37.
221. Forte P, Pazmany L, Matter-Reissmann UB, Stussi G, Schneider MK, Seebach JD. HLA-G inhibits rolling adhesion of activated human NK cells on porcine endothelial cells. J Immunol 2001 167 : 6002 6008.
222. Forte P, Baumann BC, Weiss EH, Seebach JD. HLA-E expression on porcine cells: protection from human NK cytotoxicity depends on peptide loading. Am J Transplant 2005 5 : 2085 2093.
223. Moretta A, Biassoni R, Bottino C, Mingari MC, Moretta L. Natural cytotoxicity receptors that trigger human NK cell-mediated cytolysis. Immunol Today 2000 21 : 228 234.
224. Nakamura MC, et al. Natural killing of xenogeneic cells mediated by the mouse Ly-49D receptor. J Immunol 1999 163 : 4694 4700.
225. Forte P, Lilienfeld BG, Baumann BC, Seebach JD. Human NK cytotoxicity against porcine cells is triggered by NKp44 and NKG2D. J Immunol 2005 175 : 5463 5470.
226. Christiansen D, Mouhtouris E, Milland J, Zingoni A, Santoni A, Sandrin MS. Recognition of a carbohydrate xenoepitope by human NKRP1A (CD161). Xenotransplantation 2006 13 : 440 446.
227. Raulet DH, Vance RE. Self-tolerance of natural killer cells. Nat Rev Immunol 2006 6 : 520 531.
228. Wu MF, Raulet DH. Class I-deficient hemopoietic cells and nonhemopoietic cells dominantly induce unresponsiveness of natural killer cells to class I-deficient bone marrow cells. J Immunol 1997 158 : 1628 1633.
229. Forman D, et al. Viral abrogation of stem cell transplantation tolerance causes graft rejection and host death by different mechanisms. J Immunol 2002 168 : 6047 6056.
230. Dauphinee MJ, Nordin AA. Studies of the immunological capacity of germ-free mouse radiation chimeras. IV. Cell-mediated immunity. Cell Immunol 1974 14 : 394 401.
231. Urso P, Gengozian N. T cell deficiency in mouse allogeneic radiation chimeras. J Immunol 1973 111 : 712 719.
232. Zinkernagel RM, Althage A, Cooper S, Callahan G, Klein J. In irradiation chimeras, K or D regions of the chimeric host, not of the donor lymphocytes, determine immune responsiveness of antiviral cytotoxic T cells. J Exp Med 1978 148 : 805 810.
233. Zinkernagel RM, Althage A, Callahan G, Welsh RM Jr. On the immunocompetence of H-2 incompatible irradiation bone marrow chimeras. J Immunol 1980 124 : 2356 2365.
234. Zinkernagel RM, Althage A. On the role of thymic epithelium vs. bone marrow-derived cells in repertoire selection of T cells. Proc Natl Acad Sci USA 1999 96 : 8092 8097.
235. Ruedi E, et al. Antiviral T cell competence and restriction specificty of mixed allogeneic (P1+P2 - >P1) irradiation chimeras. Cell Immuol 1989 121 : 185 195.
236. Williams MA, et al. Primary and secondary immunocompetence in mixed allogeneic chimeras. J Immunol 2003 170 : 2382 2389.
237. Koehn BH, et al. Fully MHC-disparate mixed hemopoietic chimeras show specific defects in the control of chronic viral infections. J Immunol 2007 179 : 2616 2626.
238. Williams MA, et al. Cutting edge: persistent viral infection prevents tolerance induction and escapes immune control following CD28/CD40 blockade-based regimen. J Immunol 2002 169 : 5387 5391.
239. Williams MA, et al. Characterization of virus-mediated inhibition of mixed chimerism and allospecific tolerance. J Immunol 2001 167 : 4987 4995.
240. Brehm MA, Markees TG, Daniels KA, Greiner DL, Rossini AA, Welsh RM. Direct visualization of cross-reactive effector and memory allo-specific CD8 T cells generated in response to viral infections. J Immunol 2003 170 : 4077 4086.
241. Adams AB, et al. Heterologous immunity provides a potent barrier to transplantation tolerance. J Clin Invest 2003 111 : 1887 1895.
242. Koyama I, et al. Depletion of CD8 memory T cells for induction of tolerance of a previously transplanted kidney allograft. Am J Transplant 2007 7 : 1055 1061.
243. Shirasugi N, et al. Prevention of chronic rejection in murine cardiac allografts: a comparison of chimerism- and nonchimerism-inducing costimulation blockade-based tolerance induction regimens. J Immunol 2002 169 : 2677 2684.
244. Kirk AD, et al. CTLA4-Ig and anti-CD40 ligand prevent renal allograft rejection in primates. Proc Natl Acad Sci USA 1997 94 : 8789 8798.
245. Kirk AD, et al. Induction therapy with monoclonal antibodies specific for cd80 and cd86 delays the onset of acute renal allograft rejection in non-human primates1. Transplantation 2001 72 : 377 384.
246. Elster EA, et al. Treatment with the humanized CD154-specific monoclonal antibody, hu5C8, prevents acute rejection of primary skin allografts in nonhuman primates. Transplantation 2001 72 : 1473 1478.
247. Preston E, Xu H, Dhanireddy K, Pearl J, Leopardi F, Starost M, Hale A, Kirk A. IDEC-131 (anti-CD154), sirolimus and donor-specific transfusion facilitate operational tolerance in non-human primates. Am J Transplant 2005 5 : 1032 1041.
248. Isobe M, Yagita H, Okumura K, Ihara A. Specific acceptance of cardiac allograft after treatment with antibodies to ICAM-1 and LFA-1. Science 1992 255 : 1125 1127.
249. Bushell A, Pearson TC, Morris PJ, Wood KJ. Donor-recipient microchimerism is not required for tolerance induction following recipient pretreatment with donor-specific transfusion and anti-CD4 antibody. Transplantation 1995 59 : 1367 1371.
250. van Maurik A, Wood KJ, Jones ND. Impact of both donor and recipient strains on cardiac allograft survival after blockade of the CD40-CD154 costimulatory pathway. Transplantation 2002 74 : 740 743.
251. Hall BM, et al. Anti-CD4 monoclonal antibody-induced tolerance to MHC-incompatible cardiac allografts by CD4+ suppressor T cells that are not dependent upon IL-4. J Immunol 1998 161 : 5147 5156.
252. Qian S, et al. Apoptosis within spontaneously accepted mouse liver allografts. Evidence for deletion of cytotoxic T cells and implications for tolerance induction. J Immuno 1997 158 : 4654 4661.
253. Zhang Z, et al. Pattern of liver, kidney, heart, and intestine allograft rejection in different mouse strain combinations. Transplantation 1996 62 : 1267 1272.
254. Jones ND, et al. Differential susceptibility of heart, skin, and Islet allografts to T cell-mediated rejection. J Immunol 2001 166 : 2824 2830.
255. Guo Z, et al. Long-term survival of intestinal allografts induced by costimulation blockade, busulfan and donor bone marrow infusion. Am J Transplant 2003 3 : 1091 1098.
256. Fuchimoto Y, et al. Mixed chimerism and tolerance without whole body irradiation in a large animal model. J Clin Invest 2000 105 : 1779 1789.
257. Kimikawa M, Sachs DH, COLVIN RB, Bartholemew A, Kawai T, Cosimi AB. Modifications of the conditioning regimen for achieving mixed chimerism and donor-specific tolerance in cynomolgus monkeys. Transplantation 1997 64 : 709 716.
258. Kawai T, Sachs DH, Cosimi AB. Tolerance to vascularized organ allografts in large animal models. Curr Opin Immunol 1999 11 : 516 526.
259. Kawai T, et al. Long-term outcome and alloantibody production in a non-myeloablative regimen for induction of renal allograft tolerance. Transplantation 1999 68 : 1767 1775.
260. Fudaba Y, et al. Myeloma responses and tolerance following combined kidney and nonmyeloablative marrow transplantation: in vivo and in vitro analyses. Am J Transplant 2006 6 : 2121 2133.
261. Dey BR, et al. Impact of prophlactic donor leukocyte infusions on mixed chimerism, graft-vs-host disease and anti-tumor response in patients with advanced hematologic malignancies treated with nonmyeloablative conditioning and allogeneic bone marrow transplantation. Biol Blood Marrow Transplant 2003 9 : 320 329.
262. Kawai T, et al. HLA-mismatched renal transplantation without maintenance immunosuppression. New Engl J Med 2008 358 : 353 361.
263. Scandling J, et al. Tolerance and chimerism after renal and hematopoietic-cell transplantation. N Engl J Med 2008 358 : 407 411.
264. Strober S. Protective conditioning against GVHD and graft rejection after combined organ and hematopoietic cell transplantation. Blood Cells Mol Dis 2008 40 : 48 54.
265. Shaffer J, et al. Regulatory T-cell recovery in recipients of haploidentical nonmyeloablative hematopoietic cell transplantation with a humanized anti-CD2 mAb, MEDI-507, with or without fludarabine. Exp Hematol 2007 35 : 1140 1152.
266. Tyndall A, Saccardi R. Haematopoietic stem cell transplantation in the treatment of severe autoimmune disease: results from phase I/II studies, prospective randomized trials and future directions. Clin Exp Immunol 2005 141 : 1 9.
267. Burt RK, et al. Randomized controlled trials of autologous hematopoietic stem cell transplantation for autoimmune diseases: the evolution from myeloablative to lymphoablative transplant regimens. Arthritis Rheum 2006 54 : 3750 3760.
268. Voltarelli JC, et al. Autologous nonmyeloablative hematopoietic stem cell transplantation in newly diagnosed type 1 diabetes mellitus. JAMA 2007 297 : 1568 1576.
269. de Kleer I, et al. Autologous stem cell transplantation for autoimmunity induces immunologic self-tolerance by reprogramming autoreactive T cells and restoring the CD4+CD25+ immune regulatory network. Blood 2006 107 : 1696 1702.
270. Ikehara S, et al. Organ-specific and systemic autoimmune diseases originate from defects in hematopoietic stem cells. Proc Natl Acad Sci USA 1990 87 : 8341 8344.
271. Van Wijmeersch B, et al. Allogeneic bone marrow transplantation in models of experimental autoimmune encephalomyelitis: evidence for a graft-versus-autoimmunity effect. Biol Blood Marrow Transplant 2007 13 : 627 637.
272. Hinterberger W, Hinterberger-Fischer M, Marmont A. Clinically demonstrable anti-autoimmunity mediated by allogeneic immune cells favorably affects outcome after stem cell transplantation in human autoimmune diseases. Bone Marrow Transplant 2002 30 : 753 759.
273. Nikolic B, Takeuchi Y, Leykin I, Fudaba Y, Smith RN, Sykes M. Mixed hematopoietic chimerism induced with non-myeloablative conditioning allows cure of autoimmune diabetes through allogeneic tolerance and reversal of autoimmunity. Diabetes 2004 53 : 376 383.
274. Sykes M, Nikolic B. Treatment of severe autoimmune disease by stem-cell transplantation. Nature 2005 435 : 620 627.
275. Griffith LM, et al. Target populations in allogeneic hematopoietic cell transplantation for autoimmune diseases - a workshop accompanying: cellular therapy for treatment of autoimmune diseases, basic science and clinical studies, including new developments in hematopoietic and mesenchymal stem cell therapy. Biol Blood Marrow Transplant 2006 12 : 688 690.