Characterization of peripheral autoregulatory mechanisms that prevent development of cyclosporin-induced syngeneic graft-versus-host disease.
Administration of cyclosporin after syngeneic bone marrow transplantation paradoxically elicits a T lymphocyte-dependent autoaggression syndrome termed syngeneic graft-vs-host disease (SGVHD). The induction of SGVHD requires two essential components, the emergence of autoreactive lymphocytes from the thymus and the elimination of a T cell-dependent peripheral autoregulatory mechanism. These studies used the SGVHD model to further characterize this regulatory system that modifies the autoimmune potential of autoreactive effector cells. Our studies reveal that although cyclosporin did not interfere with the effector function of the autoregulatory T cells, it prevented the reconstitution of the regulatory system after syngeneic bone marrow transplantation. Furthermore, the autoregulation of SGVHD is a dynamic process specifically recognizing and responding to the autoreactive SGVHD effector cells. Challenge or priming of normal Lewis rats by intravenous infusion of irradiated SGVHD effector cells activates and amplifies this autoregulatory system resulting in: 1) a threefold enhancement of autoregulatory T cell function, 2) the appearance of a dominant autoregulatory T cell population belonging to the CD4+ T helper lymphocyte subset, and 3) the capacity of irradiated primed autoregulatory T cells to inactivate SGVHD effector lymphocytes in vitro. Additional studies reveal that effective autoregulation required a specific interaction of the TCR-alpha/beta on the autoregulatory cells with the MHC class II determinants on the autoreactive lymphocytes.
Hess
A D
AD
Bone Marrow Transplant Unit, Johns Hopkins University, Baltimore, MD 21287.
Fischer
A C
AC
Horwitz
L
L
Bright
E C
EC
Laulis
M K
MK
D000818:Animals; D016026:Bone Marrow Transplantation / Q000276:immunology*; D016572:Cyclosporine / Q000494:pharmacology*; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology*; D007116:Immunization, Passive; D066298:In Vitro Techniques; D007376:Interleukin-2 / Q000494:pharmacology; D008213:Lymphocyte Activation; D051381:Rats; D011917:Rats, Inbred Lew; D011920:Rats, Inbred WF; D013601:T-Lymphocytes / Q000276:immunology*
D007376:Interleukin-2; D016572:Cyclosporine