The Journal of Immunology, Vol 145, Issue 2 526-533, Copyright © 1990 by American Association of Immunologists

ARTICLES

Effector mechanisms in cyclosporine A-induced syngeneic graft-versus- host disease. Role of CD4+ and CD8+ T lymphocyte subsets

AD Hess, AC Fischer and WE Beschorner
Bone Marrow Transplant Unit, Johns Hopkins University, Baltimore, MD 21205.

Syngeneic graft-versus-host disease (SGVHD) is a T cell-mediated autoimmune disease occurring postsyngeneic bone marrow transplantation and the administration of the potent immunosuppressive agent, cyclosporine A. Paradoxically, cyclosporine A disrupts the immunologic homeostasis governing self-tolerance. Our studies using an adoptive transfer model attempted to identify effector mechanisms associated with the autoimmune disease. Both CD4+ and CD8+ splenic T cells isolated from autoimmune donors were required for the adoptive transfer of active disease into lethally irradiated secondary recipients reconstituted with normal bone marrow. Doses of more than 5 x 10(6) of nylon wool depleted splenocytes from autoimmune donors effectively transferred disease into lethally irradiated secondary recipients. Splenocytes that are T cell depleted or CD4(+)-enriched cells did not elicit disease upon adoptive transfer. Nylon wool fractionated CD8+ splenocytes also failed to adoptively transfer disease unless high doses (greater than or equal to 30 x 10(6)) were used. The disease transferred with the CD8+ subset presented as acute type SGVHD and was self-limiting. The recombination of the individually isolated T cell subsets not only restored but also enhanced immune reactivity upon adoptive transfer. Moreover, use of the recombined subsets resulted in progressive disease with the development of chronic type SGVHD. The titration of each subset to the other suggested that a minimal number of CD4+ T cells was required to potentiate the CD8+ autoreactive cells in vivo. Further analysis of the helper cell involved demonstrated that it had a CD4+ CD45r- phenotype, characteristic of an amplifying helper cell population. Administration of IL-2 did not substitute for CD4+ Th cells but yet amplified the activity of unfractionated cells or recombined subsets implicating the role of other factors in the pathogenesis of SGVHD. Delineation of the effector mechanisms involved in SGVHD is critical in determining the underlying events that trigger either the production of autoreactive cells or the perturbation of the regulation of these autoreactive cells, culminating in autoimmunity.

This article has been cited by other articles:

				J. S. Bryson, C. D. Jennings, J. A. Brandon, J. Perez, B. E. Caywood, and A. M. Kaplan Adoptive transfer of murine syngeneic graft-vs.-host disease by CD4+ T cells J. Leukoc. Biol., December 1, 2007; 82(6): 1393 - 1400. [Abstract] [Full Text] [PDF]

				Y. Sakoda, D. Hashimoto, S. Asakura, K. Takeuchi, M. Harada, M. Tanimoto, and T. Teshima Donor-derived thymic-dependent T cells cause chronic graft-versus-host disease Blood, February 15, 2007; 109(4): 1756 - 1764. [Abstract] [Full Text] [PDF]

				R Cimaz Any increased risk of autoimmune disease? Lupus, September 1, 2004; 13(9): 736 - 739. [Abstract] [PDF]

				J. S. Bryson, L. Zhang, S. W. Goes, C. D. Jennings, B. E. Caywood, S. L. Carlson, and A. M. Kaplan CD4+ T Cells Mediate Murine Syngeneic Graft-versus-Host Disease-Associated Colitis J. Immunol., January 1, 2004; 172(1): 679 - 687. [Abstract] [Full Text] [PDF]

				Y. Miura, C. J. Thoburn, E. C. Bright, W. Chen, S. Nakao, and A. D. Hess Cytokine and chemokine profiles in autologous graft-versus-host disease (GVHD): interleukin 10 and interferon gamma may be critical mediators for the development of autologous GVHD Blood, September 18, 2002; 100(7): 2650 - 2658. [Abstract] [Full Text] [PDF]

				D. Y. Wu and I. Goldschneider Tolerance to Cyclosporin A-Induced Autologous Graft-Versus-Host Disease Is Mediated by a CD4+CD25+ Subset of Recent Thymic Emigrants J. Immunol., June 15, 2001; 166(12): 7158 - 7164. [Abstract] [Full Text] [PDF]

				W. Chen, C. Thoburn, and A. D. Hess Characterization of the Pathogenic Autoreactive T Cells in Cyclosporine-Induced Syngeneic Graft-Versus-Host Disease J. Immunol., December 15, 1998; 161(12): 7040 - 7046. [Abstract] [Full Text] [PDF]