Separation of major histocompatibility complex (MHC) and non-MHC gene effects in the development of T cell subsets in relation to susceptibility to cyclosporine A-induced autoimmunity

• Published in: Transplantation proceedings 1997-05, Vol.29 (3), p.1690-1691
• Main Authors: Damoiseaux, J.G.M.C., Beijleveld, L.J.J., van Breda Vriesman, P.J.C.
• Format: Article
• Language: English
• Subjects: Animals; Autoimmune Diseases - chemically induced; Autoimmune Diseases - genetics; Biological and medical sciences; Bone Marrow Transplantation - immunology; Cyclosporine - pharmacology; Disease Susceptibility; Experimental and animal immunopathology. Animal models; Flow Cytometry; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Immunopathology; Immunophenotyping; Immunosuppressive Agents - pharmacology; Major Histocompatibility Complex; Medical sciences; Rats; Rats, Inbred BN; Rats, Inbred Lew; T-Lymphocyte Subsets - drug effects; T-Lymphocyte Subsets - immunology; Tissue, organ and graft immunology; Transplantation, Isogeneic
• ISSN: 0041-1345; 1873-2623
• DOI: 10.1016/S0041-1345(97)00017-1

Many experimental models for autoimmune disease share the requirement of immunization with the respective autoantigen. Activation of potentially autoreactive cells, already present in the peripheral immune system, results in development of disease. Susceptibility and resistance of this type of autoimmune models depend on both major histocompatibility complex (MHC) and non-MHC encoded genes. 1−3 MHC-genes are likely to be involved in presentation of the proper antigenic peptide, whereas non-MHC genes are supposed to be involved in an active process of suppression. 4 T cells are prevented from displaying their autoreactive potential by other antagonizing T cells. 5,6 An alternative way to induce autoimmunity is achieved by total body irradiation (TBI) and subsequent syngeneic bone marrow transplantation (BMT) followed by a 4-week period of daily Cyclosporine-A (CyA) administration. 7 After cessation of CyA therapy an autoimmune disease similar to graft-versus-host disease develops which is referred to as CyA-induced autoimmunity (CyA-AI); in the chronic phase the model has many similarities with human scleroderma. 8–10 In this model CyA is thought to interfere with negative selection in the thymus resulting in an increased output of self-reactive cells, whereas irradiation is required for the elimination of the peripheral autoregulatory T cell circuit. 11 CyA-AI susceptible Lewis (LEW) rats and CyA-AI resistant Brown Norway (BN) rats differ greatly in the composition of their peripheral T cell subsets. 12,13 To dissect the role of MHC and non-MHC genes on the development of peripheral T cell ratios in relation to susceptibility for CyA-AI, the respective MHC congenic strains (LEW-1N and BN-1L) were examined for their composition of T cell subsets and for their ability to develop clinical and histological CyA-AI.