title: Helper T lymphocyte unresponsiveness to cardiac allografts following transient depletion of CD4-positive cells. Implications for cellular and humoral responses.
abstract: Initial treatment of heterotopic cardiac transplant recipients with anti-CD4 mAb promotes long-term (> 60 days) allograft survival. We have used modified limiting dilution analysis to quantitate donor alloantigen-reactive helper T lymphocytes (HTL) and CTL in mice bearing long-term cardiac allografts. Despite repopulation of lymphoid tissues with CD4+ T cells, donor alloantigen-reactive IL-2 producing and IL-4-producing HTL were rare or not detectable in lymphoid tissues or in the graft. While donor-reactive precursor CTL were present in lymphoid tissues, modified limiting dilution analysis revealed that stimulated ("antigen-conditioned") CTL were not detectable, and few CTL were present in the graft. In addition, antibodies reactive with donor alloantigens were not detectable in the sera of mice bearing long-term cardiac allografts. To determine whether additional in vivo stimulation with donor alloantigens would elicit an immune response, sponge allografts were implanted into mice bearing long-term cardiac allografts. Previous reports from this laboratory have demonstrated that T cell infiltration of sponge allografts is dependent upon antigen-driven cytokine production. While third-party sponge allografts were readily infiltrated by third-party-reactive HTL and CTL, sponge allografts of the same strain as the cardiac allograft were not infiltrated by T cells. However, donor strain sponge allografts induced an IgM (but not IgG) alloantibody response. These data indicate that IgM alloantibody could be induced in the absence of a cellular response to the sponge allograft. Kinetic studies revealed that a transient IgM (but not IgG) response was induced by the initial cardiac transplantation in the absence of CD4+ cells. These IgM alloantibodies disappeared by day 21 despite the persistence of the allograft. These observations indicate that transient depletion of CD4+ T cells induces allograft-specific T cell tolerance, but does not eliminate the ability to mount an allograft-specific IgM response. To our knowledge, this is the first report of a transient humoral response to alloantigens that occurs in the absence of CD4+ T cells, and can be reinduced in "tolerant" animals that fail to mount a cellular immune response. Potential mechanisms involved in the development and maintenance of anti-CD4 mAb-induced tolerance are discussed.
authors.affiliation: Section of Thoracic Surgery, University of Michigan School of Medicine, Ann Arbor 48109.
authors.forename: D K
authors.initials: DK
authors.lastname: Bishop
authors.forename: W
authors.initials: W
authors.lastname: Li
authors.forename: S Y
authors.initials: SY
authors.lastname: Chan
authors.forename: R D
authors.initials: RD
authors.lastname: Ensley
authors.forename: J
authors.initials: J
authors.lastname: Shelby
authors.forename: E J
authors.initials: EJ
authors.lastname: Eichwald
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000917:Antibody Formation / Q000276:immunology; D015704:CD4 Antigens / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D000939:Epitopes; D005260:Female; D016027:Heart Transplantation / Q000276:immunology*; D007111:Immunity, Cellular / Q000276:immunology; D007132:Immunoglobulin Isotypes / Q000097:blood / Q000276:immunology; D007075:Immunoglobulin M / Q000096:biosynthesis / Q000097:blood / Q000276:immunology; D007376:Interleukin-2 / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis; D007518:Isoantibodies / Q000096:biosynthesis / Q000097:blood / Q000276:immunology; D007519:Isoantigens / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D013154:Spleen / Q000166:cytology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000378:metabolism; D014019:Tissue Donors
chemical_list: D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D000939:Epitopes; D007132:Immunoglobulin Isotypes; D007075:Immunoglobulin M; D007376:Interleukin-2; D007518:Isoantibodies; D007519:Isoantigens; D015847:Interleukin-4