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Non-Myeloblative Induction of Mixed Hematopoietic Chimerism: Application to Transplantation Tolerance and Hematologic Malignancies in Experimental and Clinical Studies

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Non-Myeloablative Allogeneic Transplantation

Part of the book series: Cancer Treatment and Research ((CTAR,volume 110))

Abstract

This cyclophosphamide-based non-myeloablative preparative regimen for HLA-matched or -mismatched allogeneic bone marrow transplantation is generally well-tolerated and has been associated with striking anti-tumor responses in some recipients with chemorefractory hematologic malignancies. GVHD has occurred in a minority of recipients of HLA-matched donor transplants (prior to prophylactic DLI); the high incidence of GVHD following HLA- mismatched donor transplants in which ATG was utilized suggest inadequate in vivo T cell depletion in these cases. Graft rejection in the HLA-matched donor transplant setting, which has occurred in a significant percentage of patients, may be associated with a suboptimal anti-tumor response. Sustained anti-tumor responses with minimal GVHD have been seen in some recipients of prophylactic DLI. However, GVHD, when it has occurred, has sometimes been severe. It may be important to revise the schedule and perhaps dosing of DLI according to patterns of chimerism (increasing or decreasing) and the underlying disease (indolent versus aggressive).

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References

  1. Madsen, J.C., Yamada, K., Allan, J.S., Choo, J.K., Erhorn, A.E., Pins, M.R., Vesga, L., Slisz, J.K., and Sachs, D.H. (1998): Transplantation tolerance prevents cardiac graft vasculopathy in major histocompatiblity complex class I-disparate miniature swine.Transplantation65:304–313.

    Article  PubMed  CAS  Google Scholar 

  2. Orloff, M.S., DeMara, E.M., Coppage, M.L., Leong, N., Fallon, M.A., Sickel, J., Zuo, X.-J., Prehn, J., and Jordan, S.C. (1995): Prevention of chronic rejection and graft arteriosclerosis by tolerance induction.Transplantation59:282–288.

    PubMed  CAS  Google Scholar 

  3. Colson, Y.L., Zadach, K., Nalesnik, M., and Ildstad, S.T. (1995): Mixed allogeneic chimerism in the rat. Donor-specific transplantation tolerance without chronic rejection for primarily vascularized cardiac allografts.Transplantation60:971–980.

    PubMed  CAS  Google Scholar 

  4. Sykes, M., Sheard, M.A., and Sachs, D.H. (1988): Graft-versus-hostrelated immunosuppression is induced in mixed chimeras by alloresponses against either host or donor lymphohematopoietic cells.J.Exp.Med.168:2391–2396.

    Article  PubMed  CAS  Google Scholar 

  5. Sharabi, Y. and Sachs, D.H. (1989): Mixed chimerism and permanent specific transplantation tolerance induced by a non-lethal preparative regimen.J.Exp.Med.169:493–502.

    Article  PubMed  CAS  Google Scholar 

  6. Tomita, Y., Sachs, D.H., Khan, A., and Sykes, M. (1996): 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.Transplantation61:469–477.

    Article  PubMed  CAS  Google Scholar 

  7. Pelot, M.R., Pearson, D.A., Swenson, K., Zhao, G., Sachs, J., Yang, Y.-G., and Sykes, M. (1999): Lymphohematopoietic graft-vs-host reactions can be induced without graft-vs-host disease in murine mixed chimeras established with a cyclophosphamidebased non-myeloablative conditioning regimen.Biol.Blood Marrow Transplant.5:133–143.

    Article  PubMed  CAS  Google Scholar 

  8. Owen, R.D. (1945): Immunogenetic consequences of vascular anastomoses between bovine twins.Science102:400–401.

    Article  PubMed  CAS  Google Scholar 

  9. Anderson, D., Billingham, R.E., Lampkin, G.H., and Medawar, P.B. (1951): The use of skin grafting to distinguish between monozygotic and dizygotic twins in cattle.Heredity5:379397.

    Google Scholar 

  10. Billingham, R.E., Lampkin, G.H., Medawar, P.B., and Williams, H.LI. (1952): Tolerance to homografts, twin diagnosis, and the freemartin condition in cattle.Heredity6:201–212.

    Article  Google Scholar 

  11. Billingham, R.E., Brent, L., and Medawar, P.B. (1953): “Actively acquired tolerance” of foreign cells.Nature172:603–606.

    Article  PubMed  CAS  Google Scholar 

  12. .Main, J.M. and Prehn, R.T. (1955): Successful skin homografts after the administration of high dosage X radiation and homologous bone marrow.J Natl. Cancer Inst. 1023-1028.

    Google Scholar 

  13. Singer, A., Hathcock, K.S., and Hodes, R.J. (1981): Self recognition in allogeneic radiation chimeras. A radiation resistant host 94 element dictates the self specificity and immune response gene phenotype of T-helper cells.J.Exp.Med.153:1286–1301.

    Article  PubMed  CAS  Google Scholar 

  14. Zinkernagel, R.M., Callahan, G.N., Althage, A., Cooper, S., Klein, P.A., and Klein, J. (1978): On the thymus in the differentiation of “H-2 self-recognition” by T cells: evidence for dual recognition?1Exp.Med.147:882–896.

    Article  CAS  Google Scholar 

  15. Zinkernagel, R.M., Althage, A., Callahan, G., and Welsh Jr., R.M. (1980): On the immunocompetence of H-2 incompatible irradiation bone marrow chimeras.J.Immunol.124:2356–2365.

    PubMed  CAS  Google Scholar 

  16. Ildstad, S.T., Wren, S.M., Bluestone, J.A., Barbieri, S.A., and Sachs, D.H. (1985): Characterization of mixed allogeneic chimeras. Immunocompetence, in vitro reactivity, and genetic specificity of tolerance.J.Exp.Med.162:231–244.

    Article  PubMed  CAS  Google Scholar 

  17. Slavin, S., Strober, S., Fuks, Z., and Kaplan, H.S. (1977): Induction of specific tissue transplantation tolerance using fractionated total lymphoid irradiation in adult mice: long-term survival of allogeneic bone marrow and skin grafts.J.Exp.Med.146:34

    Article  PubMed  CAS  Google Scholar 

  18. Slavin, S., Fuks, Z., Kaplan, H.S., and Strober, S. (1978): Transplantation of allogeneic bone marrow without graftversus-host disease using total lymphoid irradiation.JExp.Med.147:963–972.

    Article  CAS  Google Scholar 

  19. Slavin, S., Reitz, B., Bieber, C.P., Kaplan, H.S., and Strober, S. (1978): Transplantation tolerance in adult rats using total lymphoid irradiation: permanent survival of skin, heart, and marrow allografts.J.Exp.Med.147:700–707.

    Article  PubMed  CAS  Google Scholar 

  20. Vallera, D.A., Soderling, C.C.B., Carlson, G.J., and Kersey, J.H. (1982): Bone marrow transplantation across major histocompatibility barriers in mice. II. T cell requirement for engraftment in toltal lymphoid irradiation-conditioned recipients.Transplantation33:243–248.

    Article  PubMed  CAS  Google Scholar 

  21. Ildstad, S.T. and Sachs, D.H. (1984): Reconstitution with syngeneic plus allogeneic or xenogeneic bone marrow leads to specific acceptance of allografts or xenografts.Nature307(5947):168–170.

    Article  PubMed  CAS  Google Scholar 

  22. Ruedi, E., Sykes, M., Ildstad, S.T., Chester, C.H., Althage, A., Hengartner, H., Sachs, D.H., and Zinkernagel, R.M. (1989): 95 Antiviral T cell competence and restriction specificty of mixed allogeneic (Pl+P2-->P1) irradiation chimeras.Cell.Immuol.121:185–195.

    Article  CAS  Google Scholar 

  23. Anasetti, C., Amos, D., Beatty, P.G., Appelbaum, F.R., Bensinger, W., Buckner, C.D., Clift, R., Doney, C., Martin, P.J., Mickelson, E., Nisperos, B., O’Quigley, J., Ramberg, R., Sanders, J.E., Stewart, P., Storb, R., Sullivan, K.M., Witherspoon, R.P., Thomas, E.D., and Hansen, J.A. (1989): Effect of HLA compatibility on engraftment of bone marrow transplants in patients with leukemia or lymphoma.New Engl.J.Med.320:197–204.

    Article  PubMed  CAS  Google Scholar 

  24. Kernan, N.A., Flomenberg, N., Dupont, B., and O’Reilly, R.J. (1987): Graft rejection in recipients of T-cell-depleted HLAnonidentical marrow transplants for leukemia.Transplantation43:842–847.

    PubMed  CAS  Google Scholar 

  25. Clift, R.A. and Storb, R. (1987): Histoincompatible bone marrow transplants in humans.Ann.Rev.Immunol.5:43–64.

    Article  CAS  Google Scholar 

  26. Cobbold, S.P., Martin, G., Qin, S., and Waldmann, H. (1986): Monoclonal antibodies to promote marrow engraftment and tissue graft tolerance.Nature323:164–165.

    Article  PubMed  CAS  Google Scholar 

  27. Tomita, Y., Sachs, D.H., and Sykes, M. (1994): Myelosuppressive conditioning is required to achieve engraftment of pluripotent stem cells contained in moderate doses of syngeneic bone marrow.Blood83:939–948.

    PubMed  CAS  Google Scholar 

  28. Tomita, Y., Khan, A., and Sykes, M. (1996): 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.Transplantation61:477–485.

    Article  PubMed  CAS  Google Scholar 

  29. Sykes, M., Szot, G.L., Swenson, K., and Pearson, D.A. (1997): Induction of high levels of allogeneic hematopoietic reconstitution and donor-specific tolerance without myelosuppressive conditioning.Nature Med.3:783–787.

    Article  PubMed  CAS  Google Scholar 

  30. Wekerle, T., Sayegh, M.H., Hill, J., Zhao, Y., Chandraker, A., Swenson, K.G., Zhao, G., and Sykes, M. (1998): Extrathymic T cell deletion and allogeneic stem cell engraftment induced with 96 costimulatory blockade is followed by central T cell tolerance.J.Exp.Med.187:2037–2044.

    Article  PubMed  CAS  Google Scholar 

  31. Wekerle, T., Sayegh, M.H., Ito, H., Hill, J., Chandraker, A., Pearson, D.A., Swenson, K.G., Zhao, G., and Sykes, M. (1999): AntiCD154 or CTLA4Ig obviates the need for thymic irradiation in a non-myeloablative conditioning regimen for the induction of mixed hematopoietic chimerism and tolerance.Transplantation68:1348–1355.

    Article  PubMed  CAS  Google Scholar 

  32. Wekerle, T., Kurtz, J., Ito, H., Ronquillo, J.V., Dong, V., Zhao, G., Shaffer, J., Sayegh, M.H., and Sykes, M. (2000): Allogeneic bone marrow translantation with costimulatory blockade induces macrochimerism and tolerance without cytoreductive host treatment.Nature Med.6:464–469.

    Article  PubMed  CAS  Google Scholar 

  33. Ardavin, C., Wu, L., Li, C.-L., and Shortman, K. (1993): Thymic dendritic cells and T cells develop simultaneously in the thymus from a common precursor population.Nature362:761–763.

    Article  PubMed  CAS  Google Scholar 

  34. Brocker, T., Riedinger, M., and Karjalainen, K. (1997): Targeted expression of major histocompatibiity complex (MHC) class II molecules demonstrates that dendritic cells can induce negative but not positive selection of thymocytes in vivo.J.Exp.Med.185:541–550.

    Article  PubMed  CAS  Google Scholar 

  35. Inaba, M., Inaba, K., Hosono, M., Kumamoto, T., Ishida, T., Muramatsu, S., Masuda, T., and Ikehara, S. (1991): Distinct mechanisms of neonatal tolerance induced by dendritic cells and thymic B cells.iExp.Med.173:549–559.

    Article  CAS  Google Scholar 

  36. Tomita, Y., Khan, A., and Sykes, M. (1994): 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.153:1087–1098.

    PubMed  CAS  Google Scholar 

  37. Manilay, J.O., Pearson, D.A., Sergio, J.J., Swenson, K.G., and Sykes, M. (1998): Intrathymic deletion of alloreactive T cells in mixed bone marrow chimeras prepared with a nonmyeloablative conditioning regimen.Transplantation66:96–102.

    Article  PubMed  CAS  Google Scholar 

  38. Khan, A., Tomita, Y., and Sykes, M. (1996): Thymic dependence of loss of tolerance in mixed allogeneic bone marrow chimeras after depletion of donor antigen. Peripheral mechanisms do not 97 contribute to maintenance of tolerance.Transplantation62:380–387.

    Article  PubMed  CAS  Google Scholar 

  39. Murphy, W.J., Kumar, V., and Bennett, M. (1987): Rejection of bone marrow allografts by mice with severe combined immune deficiency (scid). Evidence that natural killer cells can mediate the specificity of marrow graft rejection.J.Exp.Med.165:1212–1217.

    Article  PubMed  CAS  Google Scholar 

  40. Kiessling, R., Hochman, P.S., Haller, O., Shearer, G.M., Wigzell, H., and Cudkowicz, G. (1977): Evidence for a similar or common mechanism for natural killer activity and resistance to hemopoietic grafts.Eur.J.Immunol.7:655–663.

    Article  PubMed  CAS  Google Scholar 

  41. Lee, L.A., Sergio, J.J., and Sykes, M. (1996): Natural killer cells weakly resist engraftment of allogeneic long-term multilineagerepopulating hematopoietic stem cells.Transplantation61:125–132.

    Article  PubMed  CAS  Google Scholar 

  42. Shizuru, J.A., Jerabek, L., Edwards, C.T., and Weissman, I.L. (1996): Transplantation of purified hematopoietic stem cells: requirements for overcoming the barriers of allogeneic engraftment.Biol.Blood Marrow Transplant.2:3–14.

    PubMed  CAS  Google Scholar 

  43. Sharabi, Y., Aksentijevich, I., Sundt III, T.M., Sachs, D.H., and Sykes, M. (1990): Specific tolerance induction across a xenogeneic barrier: production of mixed rat/mouse lymphohematopoietic chimeras using a nonlethal preparative regimen.J.Exp.Med.172:195–202.

    Article  PubMed  CAS  Google Scholar 

  44. Nikolic, B., Cooke, D.T., Zhao, G., and Sykes, M. (2000):Both y/8T cells and NK cells inhibit the engraftment of xenogeneic rat bone marrow cells in mice.(Submitted)

    Google Scholar 

  45. Sykes, M., Eisenthal, A., and Sachs, D.H. (1988): Mechanism of protection from graft-vs-host disease in murine mixed allogeneic chimeras. I. Development of a null cell population suppressive of cell-mediated lympholysis responses and derived from the syngeneic bone marrow component.J.Immunol.140:2903–2911.

    PubMed  CAS  Google Scholar 

  46. Ildstad, S.T., Wren, S.M., Bluestone, J.A., Barbieri, S.A., Stephany, D., and Sachs, D.H. (1986): Effect of selective T cell depletion of host and/or donor bone marrow on lymphopoietic repopulation,98tolerance, and graft-vs-host disease in mixed allogeneic chimeras (B10 + B 10.D2--->B 10).JImmunol.136:28–33.

    CAS  Google Scholar 

  47. Storb, R., Yi, C., Wagner, J.L., Deeg, J., Nash, R.A., Kiem, H.-P., Leisenring, W., and Shulman, H. (1997): Stable mixed hematopietic chimerism in DLA-identical littermate dogs given sublethal total body irradiation before and pharmacological immunosuppression after marrow transplantation.Blood89:3048–3054.

    PubMed  CAS  Google Scholar 

  48. Huang, C.A., Fuchimoto, Y., Sheir-Dolberg, R., Murphy, M.C., Neville Jr., D.M., and Sachs, D.H. (2000): Stable mixed chimerism and tolerance using a non-myeloablative preparative regimen in a large animal model.J.Clin.Invest.105:173–181.

    Article  PubMed  CAS  Google Scholar 

  49. Fuchimoto, Y., Huang, C.A., Yamada, K., Shimizu, A., Kitamura, H., COLVIN, R.B., Ferrara, V., Murphy, M.C., Sykes, M., White-Scharf, M., Neville Jr., D., and Sachs, D.H. (2000): Mixed chimerism and tolerance without whole body irradiation in a large animal model.J.Clin.Invest.105:1779–1789.

    Article  PubMed  CAS  Google Scholar 

  50. Kawai, T., Cosimi, A.B., COLVIN, R.B., Powelson, J., Eason, J., Kozlowski, T., Sykes, M., Monroy, R., Tanaka, M., and Sachs, D.H. (1995): Mixed allogeneic chimerism and renal allograft tolerance in cynomologous monkeys.Transplantation59:256262.

    Google Scholar 

  51. Kimikawa, M., Sachs, D.H., COLVIN, R.B., Bartholemew, A., Kawai, T., and Cosimi, A.B. (1997): Modifications of the conditioning regimen for achieving mixed chimerism and donor-specific tolerance in cynomolgus monkeys.Transplantation64:709716.

    Google Scholar 

  52. Sykes, M. and Sachs, D.H. (1988): Mechanisms of suppression in mixed allogeneic chimeras.Transplantation.46:135S–142S.

    Article  PubMed  CAS  Google Scholar 

  53. Sykes, M. (1989): Suppressive activity in recipients of non-T-celldepleted allogeneic bone marrow transplants: role of T cell-depleted syngeneic marrow.Bone Marrow Transplant., 4Supp. 4:30–33.

    Google Scholar 

  54. Sykes, M., Sharabi, Y., and Sachs, D.H. (1990): Natural suppressor cells in spleens of irradiated, bone marrow reconstituted mice and normal bone marrow: lack of Sca-1 expression and 99 enrichment by depletion of Macl-positive cells.Cell.Immuol.127:260–274.

    Article  CAS  Google Scholar 

  55. Stavin, S. and Strober, S. (1978): Spontaneous murine B-cell leukemia.Nature272:624–626.

    Article  Google Scholar 

  56. Sykes, M., Preffer, F., McAffee, S., Saidman, S.L., Colby, C., Sackstein, R., Sachs, D.H., and Spitzer, T.R. (1999): Mixed lymphohematopoietic chimerism and graft-vs-lymphoma effects are achievable in adult humans following nonmyeloablative therapy and HLA-mismatched donor bone marrow transplantation.Lancet353:1755–1759.

    Article  PubMed  CAS  Google Scholar 

  57. Spitzer, T.R., MCafee, S., Sackstein, R., Colby, C., Dey, B., Saidman, S., Preffer, F., Alexander, S., Sachs, D.H., and Sykes, M. (2000): Mixed lymphohematopoietic chimerism and delayed donor leukocyte infusions following non-myeloablative conditioning and HLA-matched and mismatched donor bone marrow transplantation.10th Symposium on Autologous Blood and Marrow Transplantation(in press)

    Google Scholar 

  58. Toh, H.C., Spitzer, T.R., Preffer, F., MCafee, S., Dombkowski, D., Clark, J.S., Colby, C., Saidman, S., Sackstein, R., and Sykes, M. (2000):Kinetics of lymphocyte recovery in mixed allogeneic chimeras induced with a non-myeloablative conditioning regimen.(UnPub)

    Google Scholar 

  59. Spitzer, T.R., Delmonico, F., Tolkoff-Rubin, N., MCafee, S., Sackstein, R., Saidman, S., Colby, C., Sykes, M., Sachs, D.H., and Cosimi, A.B. (1999): Combined HLA-matched donor bone marrow and renal transplantation for multiple myeloma with end stage renal disease: The induction of allograft tolerance through mixed lymphohematopoietic chimerism.Transplantation68:480–484.

    Article  PubMed  CAS  Google Scholar 

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Sykes, M., Spitzer, T.R. (2002). Non-Myeloblative Induction of Mixed Hematopoietic Chimerism: Application to Transplantation Tolerance and Hematologic Malignancies in Experimental and Clinical Studies. In: Bashey, A., Ball, E.D. (eds) Non-Myeloablative Allogeneic Transplantation. Cancer Treatment and Research, vol 110. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-0919-6_4

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  • DOI: https://doi.org/10.1007/978-1-4615-0919-6_4

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