Heart allografts in murine systems. The differential activation of Th2-like effector cells in peripheral tolerance.
Activated CD4+ Th2 cells release cytokines (IL-4,-10) that block activation & cytokine (IL-2/IFN-gamma) release by proinflammatory T (CD4+,CD8+) effector cells. To test the hypothesis that peripheral tolerance to alloantigen is linked to differential activation of CD4+ Th2 cells we measured cytokine transcripts in heart grafts (C57BL/10----C3H/HeJ) and spleens of mice rendered "tolerant" by donor-specific blood transfusion, anti-CD4 mAb pretreatment, and cyclosporine administration. The expression of IL-2/IFN-gamma transcripts was reduced greater than 90% in grafts from tolerant recipients. IL-4/IL-10 transcripts were generally enhanced and persisted in graft and recipient spleen. Accordingly adoptive transfer studies were performed to determine whether Th2-like effectors, which express Fc receptors (FcR), mediate suppression in this model. Unfractionated mononuclear cells (MC) (5 x 10(6), isolated from spleens of heart graft recipients made tolerant by DST, prolonged the survival of test grafts greater than 90 days in irradiated (680 rads) recipients reconstituted with a sufficient number of MC from spleens of naive C3H to precipitate rejection of the test graft in 18.2 days (MST, n = 5). Conversely adoptive transfer of inocula depleted of FcR+ cells on immune complex columns or with anti-FcR mAb 24G2 caused test grafts to be rejected in 8-11 days. These results suggest that peripheral tolerance to alloantigen may be linked to differential activation of Th2 cells that induce anergy by suppression. The possibility that Th2-like effectors mediate peripheral tolerance to self is discussed.
Department of Medicine, Emory University School of Medicine, Atlanta, Georgia 30322.
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T
Takeuchi
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RP
Lowry
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B
Konieczny
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D001402:B-Lymphocytes / Q000276:immunology*; D015704:CD4 Antigens / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D016572:Cyclosporine / Q000008:administration & dosage; D016207:Cytokines / Q000502:physiology; D016027:Heart Transplantation / Q000276:immunology*; D006968:Hypersensitivity, Delayed / Q000276:immunology; D007108:Immune Tolerance; D016219:Immunotherapy, Adoptive; D007371:Interferon-gamma / Q000494:pharmacology; D016753:Interleukin-10 / Q000032:analysis; D007376:Interleukin-2 / Q000032:analysis; D015847:Interleukin-4 / Q000032:analysis; D008297:Male; D051379:Mice; D016133:Polymerase Chain Reaction; D011961:Receptors, Fc / Q000032:analysis; D013154:Spleen / Q000737:chemistry / Q000502:physiology; D006377:T-Lymphocytes, Helper-Inducer / Q000648:ultrastructure; D014184:Transplantation, Homologous / Q000502:physiology
D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D016207:Cytokines; D007376:Interleukin-2; D011961:Receptors, Fc; D016753:Interleukin-10; D015847:Interleukin-4; D007371:Interferon-gamma; D016572:Cyclosporine