Mixed Bone Marrow Reconstitution Across MHC Barriers



It has been known for some time that reconstitution of lethally irradiated mice with allogeneic bone marrow leads to chimerism and tolerance across major histocompatibility (MHC) barriers [1,2]. However, if mature T cells are not removed from the allogeneic bone marrow, this procedure leads also to graftversus-host disease (GVHD), which severely limits the applicability of this approach. If all mature T cells are first removed from the allogeneic bone marrow inoculum, a graft can still be achieved in mice, but in large animals, including humans [3] and miniature swine [4,5], such depletion produces major problems of failure of engraftment. The reason for this difference between rodents and large animals probably involves the much higher tolerance which mice exhibit to the toxic effects of total body irradiation (TBI) as compared to the larger species. Mice are routinely prepared for bone marrow transplantation by administration of 10 Gy TBI at 1.0 Gy/min, and the only target tissue damage which appears to be fatal is that of the lymphohematopoietic system. TBI administration at similar dose and dose rate to large animals, on the other hand, produces unacceptable levels of toxicity to other target organs, such as the gut and the lungs [6,7]. In order to develop approaches to achieving alloengraftment across MHC barriers, therefore, it is important to examine preclinical models in which T cells are not depleted from the allogeneic inoculum. We review here some of our own work with such models, including attempts to diminish the GVHD induced by allogeneic T cells without causing failure of engraftment.


Total Body Irradiation Acute GVHD Chronic GVHD Allogeneic Bone Marrow Miniature Swine 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Beverley PCL, Brent L, Brooks C, Medawar PB, Simpson E (1973) In vitro reactivity of lymphoid cells from tolerant mice. Transplant Proc 5: 679PubMedGoogle Scholar
  2. 2.
    Rayfield LS, Brent L (1983) Tolerance, immunocompetence, and secondary disease in fully allogeneic radiation chimeras. Transplantation 36: 183PubMedCrossRefGoogle Scholar
  3. 3.
    Martin PJ, Hansen JA, Torok-Storb B, Durnam D, Przepiorka D, O’Quigley J, Sanders J, Sullivan KM, Witherspoon RP, Deeg HJ, Appelbaum FR, Stewart P, Weiden P, Doney K, Buckner CD, Clift R, Storb R, Thomas ED (1988) Graft failure in patients receiving T cell-depleted HLA-identical allogeneic marrow transplants. Bone Marrow Transplant 3: 445PubMedGoogle Scholar
  4. 4.
    Popitz-Bergez FA, Sakamoto K, Pennington LR, Pescovitz MD, McDonough MA, MacVittie TJ, Gress RE, Sachs DH (1988) Bone marrow transplantation in miniature swine. II. Effect of selective genetic differences on marrow engraftment and recipient survival. Transplantation 45: 27Google Scholar
  5. 5.
    Suzuki T, Sundt TM, Kortz EO, Mixon A, Eckhaus MA, Gress RE, Spitzer TR, Sachs DH (1989) Bone marrow transplantation across an MHC barrier in miniature swine. Transplant Proc 21: 3076PubMedGoogle Scholar
  6. 6.
    Deeg HJ, Storb R, Thomas ED (1984) Bone marrow transplantation: a review of delayed complications. Br J Haematol 57: 185PubMedGoogle Scholar
  7. 7.
    Freirich EJ, Gehan EA, Rall DP, Schmidt LH, Skipper HE (1966) Quantitative comparison of toxicity of anti-cancer agents in mouse, rat, hamster, dog, monkey, and man. Cancer Chemother Rep 50: 219Google Scholar
  8. 8.
    Sykes M, Sheard M, Sachs DH (1988) Effects of T cell depletion in radiation bone marrow chimeras. I. Evidence for a donor cell population which increases allogeneic chimerism but which lacks the potential to produce GVHD. J Immunol 141: 2282Google Scholar
  9. 9.
    Ildstad ST, Wren SM, Bluestone JA, Barbieri SA, Sachs DH (1985) Characterization of mixed allogeneic chimeras. Immunocompetence, in vitro reactivty, and genetic specificity of tolerance. J Exp Med 162: 231Google Scholar
  10. 10.
    Sykes M, Chester CH, Sundt TM, Romick ML, Hoyles KA, Sachs DH (1989) Effects of T cell depletion in radiation bone marrow chimeras III. Characterization of allogeneic bone marrow cell populations that increase allogeneic chimerism independenty of graftvs-host disease in mixed marrow recipients. J Immunol 143: 3503Google Scholar
  11. 11.
    Sherman LA, Randolph CP (1981) Monoclonal anti-H-2Kb antibodies detect serological differences between H-2Kb mutants. Immunogenetics 12: 183PubMedCrossRefGoogle Scholar
  12. 12.
    Goodman JW, Burch KT, Basford NB (1972) Graft-vs-host activity of thymocytes: relationship to the role of thymocytes in hemopoiesis. Blood 39: 851Google Scholar
  13. 13.
    Goodman JW, Basford NL, Shinpock SG, Chambers ZE (1978) An amplifier cell in hemopoiesis. Exp Hematol 6: 151PubMedGoogle Scholar
  14. 14.
    Ildstad ST, Wren SM, Bluestone JA, Barbieri SA, Stephany D, Sachs DH (1986) Effect of selective T cell depletion of host and/or donor bone marrow on lymphopoietic repopulation, tolerance, and graft-vs-host disease in mixed allogeneic chimeras (B10 + B10.D2 → B10). J Immunol 136: 28PubMedGoogle Scholar
  15. 15.
    Sykes M, Romick ML, Hoyles KA, Sachs DH. (1990) In vivo administration of interleukin 2 plus T cell-depleted syngeneic marrow prevents graft-versus-host disease mortality and permits alloengraftment. J Exp Med 171: 645PubMedCrossRefGoogle Scholar
  16. 16.
    Sullivan KM, Witherspoon RP, Storb R, Anasetti C, Appelbaum FR, Bigelow C, Clark J, Doney K, Hill R, Loughran T, Matthews DD, Nims J, Petersen F, Sanders J, Schuning F, Shields A, Strom S, Thomas ED (1989) Chronic graft-versus-host disease: recent advances in diagnosis and treatment. In: Gale RP, Champlin R (eds) Bone marrow transplantation: current controversies. Liss, New York, p. 511Google Scholar
  17. 17.
    Seddick M, Seemayer TA, Lapp WS (1984) The graft-versus-host reaction and immune function. I. T helper cell immunodeficiency associated with graft-versus-host-induced thymic epithelial damage. Transplantation 37: 281Google Scholar
  18. 18.
    Holda JH, Maier T, Claman HN (1985) Murine graft-versus-host disease across minor barriers: immunosuppressive aspects of natural suppressor cells. Immunol Rev 88: 87PubMedCrossRefGoogle Scholar
  19. 19.
    Iwasaki T, Fujiwara H, Shearer GM, Iwasaki T (1986) Loss of proliferative capacity and T cell immune development potential by bone marrow from mice undergoing a graft-vshost reaction. J Immunol 137: 3100PubMedGoogle Scholar
  20. 20.
    Ildstad ST, Sachs DH (1984) Reconstitution with syngeneic plus allogeneic or xenogeneic bone marrow leads to specific acceptance of allografts or xenografts. Nature 307 (5947): 168PubMedCrossRefGoogle Scholar
  21. 21.
    Poynton CH (1988) T cell depletion in bone marrow transplantation. Bone Marrow Transplant 3: 265PubMedGoogle Scholar
  22. 22.
    Butturini A, Gale RP (1988) T cell depletion in bone marrow transplantation for leukemia: current results and future directions. Bone Marrow Transplant 3: 265Google Scholar
  23. 23.
    Sykes M, Hoyles KA, Romick ML, Sachs DH (1990) In vitro and in vivo analysis of bone marrow-derived CD3+, CD4-, CD8-, NK1.1+ cell lines. Cell Immunol 129: 478PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin · Heidelberg 1991

Authors and Affiliations

There are no affiliations available

Personalised recommendations