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Hematopoietic chimerism and tolerance of T cells, B cells, and NK cells
Hematopoietic Chimerism and Tolerance of T Cells, B Cells, and NK Cells M. Sykes, H. Ohdan, J.O. Manilay, T. Wekerle, and Y.-G. Yang
D
URABLE tolerance is reliably achieved when allogeneic pluripotent hematopoietic stem cells (PHSC) engraft in recipients initially depleted of T lymphocytes. In mice, allogeneic or concordant xenogeneic (rat) bone marrow engraftment and tolerance can be achieved by pretreatment with depleting doses of anti-CD4 and anti-CD8 monoclonal antibodies (MAbs; and in the xenogeneic combination, anti-Thy1.2 and anti-NK1.1 MAbs), followed by 3 Gy whole body irradiation (WBI) and 7 Gy of thymic irradiation (TI).1,2 TI can be omitted from host conditioning if additional MAb treatments are given3,4 and WBI can be omitted if sufficiently high doses of allogeneic marrow are given.5 Engraftment of allogeneic PHSC in these models allows migration of donor bone marrow-derived cells to the host thymus, resulting in continual deletion of developing thymocytes with reactivity to donor and host antigens.3,5–7 Engraftment of allogeneic PHSC and permanent skin graft tolerance can also be achieved without recipient treatment with T-cell-depleting MAbs or TI if costimulatory blocking agents are given with 3 Gy WBI as the only host conditioning.15 In the xenogeneic rat 3 mouse species combination, mixed chimerism is also associated with deletional T-cell tolerance.8 –10 Additionally, it leads to tolerance at the level of B cells that make natural antibodies (NAb).11,12 In discordant species combinations such as pig to human, NAb which recognize a1,3-gal carbohydrate epitopes on the donor species present a major obstacle to xenotransplantation.13 Using a1,3-gal-deficient mice, which resemble humans in that their sera contain anti-a1,3-gal NAb, we demonstrated that induction of mixed chimerism leads to tolerance of anti-a1,3-gal NAb-producing B cells that preexisted at the time of BMT and that develop post-BMT.16 Thus, induction of mixed chimerism can lead to a state of tolerance among both T and B cells. NK cells, which play a particularly prominent role in resisting xenogeneic marrow engraftment, are both donor and host derived in mixed chimeras, and therefore must be mutually tolerant in order to maintain stable chimerism. Studies of receptors that inhibit NK cell-mediated killing upon recognition of specific MHC molecules suggest that the ability to tolerize host NK cells in mixed chimeras is affected by the
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presence of donor antigens.14 Thus, mixed chimerism has the potential to tolerize B and T cells. The ability to tolerize NK cells is less certain.17 REFERENCES 1. Sharabi Y, Sachs DH: J Exp Med 169:493, 1989 2. Sharabi Y, Aksentijevich I, Sundt III TM, et al: J Exp Med 172:195, 1990 3. Tomita Y, Khan A, Sykes M: Transplantation 61:477, 1996 4. Tomita Y, Sachs DH, Khan A, et al: Transplantation 61:469, 1996 5. Sykes M, Szot GL, Swenson K, et al: Nature Med 3:783, 1997 6. Tomita Y, Khan A, Sykes M: J Immunol 153:1087, 1994 7. Khan A, Tomita Y, Sykes M: Transplantation 62:380, 1996 8. Tomita Y, Lee LA, Sykes M: Xenotransplantation 1:109, 1994 9. Lee LA, Sergio JJ, Sykes M: Xenotransplantation 2:57, 1995 10. Nikolic B, Lei H, Pearson DA, et al: Transplantation 65: 1216, 1998 11. Aksentijevich I, Sachs DH, Sykes M: Transplantation 53: 1108, 1992 12. Lee LA, Sergio JJ, Sachs DH, et al: Transplant Proc 26:1197, 1994 13. Galili U: Immunol Today 14:480, 1993 14. Sykes M, Harty MW, Karlhofer FM, et al: J Exp Med 178:223, 1993 15. Wekerle T, Sayegh MH, Hill J, et al: J Exp Med 187:2037, 1998 16. Yang Y-G, de Goma E, Ohdan H, et al: J Exp Med 187:1335, 1998 17. Manilay JO, Waneck GL, Sykes M: Int Immunol (in press)
From the Bone Marrow Transplantation Section, Transplantation Biology Research Center, Surgical Service, Massachusetts General Hospital, Boston, Massachusetts. Supported by NIH grant R01 HL49915 and by a sponsored research agreement between Massachusetts General Hospital and Bio Transplant, Inc. Address reprint requests to M. Sykes, Bone Marrow Transplantation Section, Transplantation Biology Research Center, Surgical Service, Massachusetts General Hospital, MGH E, Bldg 149-5102, Boston, MA 02129.
© 1998 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010 Transplantation Proceedings, 30, 4020 (1998)
D
URABLE tolerance is reliably achieved when allogeneic pluripotent hematopoietic stem cells (PHSC) engraft in recipients initially depleted of T lymphocytes. In mice, allogeneic or concordant xenogeneic (rat) bone marrow engraftment and tolerance can be achieved by pretreatment with depleting doses of anti-CD4 and anti-CD8 monoclonal antibodies (MAbs; and in the xenogeneic combination, anti-Thy1.2 and anti-NK1.1 MAbs), followed by 3 Gy whole body irradiation (WBI) and 7 Gy of thymic irradiation (TI).1,2 TI can be omitted from host conditioning if additional MAb treatments are given3,4 and WBI can be omitted if sufficiently high doses of allogeneic marrow are given.5 Engraftment of allogeneic PHSC in these models allows migration of donor bone marrow-derived cells to the host thymus, resulting in continual deletion of developing thymocytes with reactivity to donor and host antigens.3,5–7 Engraftment of allogeneic PHSC and permanent skin graft tolerance can also be achieved without recipient treatment with T-cell-depleting MAbs or TI if costimulatory blocking agents are given with 3 Gy WBI as the only host conditioning.15 In the xenogeneic rat 3 mouse species combination, mixed chimerism is also associated with deletional T-cell tolerance.8 –10 Additionally, it leads to tolerance at the level of B cells that make natural antibodies (NAb).11,12 In discordant species combinations such as pig to human, NAb which recognize a1,3-gal carbohydrate epitopes on the donor species present a major obstacle to xenotransplantation.13 Using a1,3-gal-deficient mice, which resemble humans in that their sera contain anti-a1,3-gal NAb, we demonstrated that induction of mixed chimerism leads to tolerance of anti-a1,3-gal NAb-producing B cells that preexisted at the time of BMT and that develop post-BMT.16 Thus, induction of mixed chimerism can lead to a state of tolerance among both T and B cells. NK cells, which play a particularly prominent role in resisting xenogeneic marrow engraftment, are both donor and host derived in mixed chimeras, and therefore must be mutually tolerant in order to maintain stable chimerism. Studies of receptors that inhibit NK cell-mediated killing upon recognition of specific MHC molecules suggest that the ability to tolerize host NK cells in mixed chimeras is affected by the
0041-1345/98/$19.00 PII S0041-1345(98)01325-6 4020
presence of donor antigens.14 Thus, mixed chimerism has the potential to tolerize B and T cells. The ability to tolerize NK cells is less certain.17 REFERENCES 1. Sharabi Y, Sachs DH: J Exp Med 169:493, 1989 2. Sharabi Y, Aksentijevich I, Sundt III TM, et al: J Exp Med 172:195, 1990 3. Tomita Y, Khan A, Sykes M: Transplantation 61:477, 1996 4. Tomita Y, Sachs DH, Khan A, et al: Transplantation 61:469, 1996 5. Sykes M, Szot GL, Swenson K, et al: Nature Med 3:783, 1997 6. Tomita Y, Khan A, Sykes M: J Immunol 153:1087, 1994 7. Khan A, Tomita Y, Sykes M: Transplantation 62:380, 1996 8. Tomita Y, Lee LA, Sykes M: Xenotransplantation 1:109, 1994 9. Lee LA, Sergio JJ, Sykes M: Xenotransplantation 2:57, 1995 10. Nikolic B, Lei H, Pearson DA, et al: Transplantation 65: 1216, 1998 11. Aksentijevich I, Sachs DH, Sykes M: Transplantation 53: 1108, 1992 12. Lee LA, Sergio JJ, Sachs DH, et al: Transplant Proc 26:1197, 1994 13. Galili U: Immunol Today 14:480, 1993 14. Sykes M, Harty MW, Karlhofer FM, et al: J Exp Med 178:223, 1993 15. Wekerle T, Sayegh MH, Hill J, et al: J Exp Med 187:2037, 1998 16. Yang Y-G, de Goma E, Ohdan H, et al: J Exp Med 187:1335, 1998 17. Manilay JO, Waneck GL, Sykes M: Int Immunol (in press)
From the Bone Marrow Transplantation Section, Transplantation Biology Research Center, Surgical Service, Massachusetts General Hospital, Boston, Massachusetts. Supported by NIH grant R01 HL49915 and by a sponsored research agreement between Massachusetts General Hospital and Bio Transplant, Inc. Address reprint requests to M. Sykes, Bone Marrow Transplantation Section, Transplantation Biology Research Center, Surgical Service, Massachusetts General Hospital, MGH E, Bldg 149-5102, Boston, MA 02129.
© 1998 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010 Transplantation Proceedings, 30, 4020 (1998)