Effect of cyclosporine on T lymphocyte development. Relationship to syngeneic graft-versus-host disease.
This report investigates the effects of cyclosporine on the reconstitution of T lymphocytes after syngeneic bone marrow transplantation and its role in the development of a novel T cell-mediated autoimmune disease, syngeneic graft versus host disease. We analyzed the effect of CsA treatment on T lymphocyte differentiation during reconstitution after bone marrow transplantation and correlated the maturation of CD4+ and CD8+ T cell subsets with the onset of syngeneic GVHD. Administration of CsA following syngeneic bone marrow transplantation leads to a developmental arrest of mature CD4+ and CD8+ T lymphocytes in the thymus and a marked reduction in cells expressing the alpha beta T cell receptor. The reduction of CD4+ and CD8+ T cell subsets is also reflected in the peripheral lymphoid compartment with an altered CD4/CD8 ratio. Functional assessment of the cells revealed that CD8+ cells respond normally to mitogenic signalling whereas CD4+ cells exhibit marginal proliferative responses. Both subsets of T lymphocytes respond to syngeneic B lymphoblasts, comparable to the response of T lymphocytes from non-CsA-treated syngeneic BMT recipients, suggesting that autoreactive cells are produced despite CsA treatment. Following discontinuation of CsA, T cell differentiation in the thymus is rapidly restored to normal. However, concurrent with the onset of syngeneic GVHD, a compensatory insurgence of CD4+ T helper cells is observed.
Fischer
A C
AC
Bone Marrow Transplantation Unit, Johns Hopkins University, Baltimore, Maryland 21205.
Laulis
M K
MK
Horwitz
L
L
Hess
A D
AD
D000818:Animals; D000945:Antigens, Differentiation, T-Lymphocyte / Q000032:analysis; D016026:Bone Marrow Transplantation; D015704:CD4 Antigens / Q000032:analysis; D016827:CD8 Antigens; D002454:Cell Differentiation / Q000187:drug effects; D003524:Cyclosporins / Q000494:pharmacology*; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology*; D051381:Rats; D011917:Rats, Inbred Lew; D011948:Receptors, Antigen, T-Cell / Q000032:analysis; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology
D000945:Antigens, Differentiation, T-Lymphocyte; D015704:CD4 Antigens; D016827:CD8 Antigens; D003524:Cyclosporins; D011948:Receptors, Antigen, T-Cell