Immunosuppression by inhibition of cellular adhesion mediated by leukocyte function-associated antigen-1/intercellular adhesion molecule-1 in murine cardiac transplantation.
BACKGROUND
Donor alloantigen-specific tolerance to vascularized allografts can be induced by several treatments, but the immunological mechanism(s) of these effects remain unclear. One hypothesis is that allograft unresponsiveness is correlated with a shift in the pattern of expression of the T helper 1 versus T helper 2 T-cell cytokines. We report here an extensive analysis of murine cardiac allografts, during normal first set rejection and in mice treated with anti-adhesion molecule monoclonal antibodies (mAbs), a regimen that results in prolonged unresponsiveness.


METHODS
A combination of immunohistochemical staining with a panel of mAbs, and in situ hybridization with a panel of digoxigenin-labeled riboprobes, was performed on frozen-tissue sections of cardiac allografts.


RESULTS
In several strain combinations, injection of anti-leukocyte function-associated antigen-1 and anti-intercellular adhesion molecule-1, from day 0 to day 6 after transplantation, results in significant long-term survival. Examination of tolerated cardiac allografts by in situ hybridization and immunohistochemical staining shows an altered cytokine expression pattern, although the frequency of CD3 and CD4 cells is not dramatically reduced. These allografts show a decreased frequency of interferon-gamma and interleukin (IL)-2-expressing cells and a slightly increased frequency of cells expressing IL-4 and IL-10, compared with unmodified acute rejection. A direct role of these changes in T-cell cytokine expression is demonstrated by reversal of tolerance induction and rejection of the allograft by in vivo injection of either anti-IL-10 or anti-IL-4 mAb.


CONCLUSIONS
Although there are significant differences in the frequency of different cellular subsets and patterns of cytokine gene expression, these differences are quantitatively subtle, suggesting a delicately balanced immune response that can develop a pattern of specific unresponsiveness, with relatively minor alterations in the specific T-cell response.
Xu
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XY
Department of Pathology, University of Alabama at Birmingham, 35233-7331, USA.
Honjo
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Devore-Carter
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Bucy
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D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D016207:Cytokines / Q000096:biosynthesis; D006085:Graft Survival / Q000276:immunology / Q000502:physiology*; D016027:Heart Transplantation / Q000276:immunology*; D007165:Immunosuppression Therapy / Q000379:methods*; D017403:In Situ Hybridization; D018799:Intercellular Adhesion Molecule-1 / Q000276:immunology / Q000502:physiology*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000276:immunology / Q000502:physiology*; D016131:Lymphocyte Subsets / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008815:Mice, Inbred Strains; D008969:Molecular Sequence Data; D051381:Rats; D013045:Species Specificity; D013997:Time Factors; D016042:Transplantation, Heterotopic; D014184:Transplantation, Homologous
D000911:Antibodies, Monoclonal; D016207:Cytokines; D016169:Lymphocyte Function-Associated Antigen-1; D018799:Intercellular Adhesion Molecule-1