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Effects of CD28 blockade on subsets of naïve T cells in cats

Lillian R. AronsonDepartment of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104-6010.

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Kenneth J. DrobatzDepartment of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104-6010.

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Christopher A. HunterDepartment of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104-6010.

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Nicola MasonDepartment of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104-6010.

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Abstract

Objective—To determine whether human CTLA4-Ig ([hu]CTLA4-Ig) inhibits costimulation-dependent lymphocyte proliferation in vitro, compare the effects of (hu)CTLA4-Ig with cyclosporine and steroids on CD4+ and CD8+ T-cell lymphocyte proliferation, and determine whether memory T-cell function remains intact in the presence of (hu)CTLA4-Ig.

Animals—29 cats.

Procedure—Peripheral blood mononuclear cells (PBMCs) were stimulated with concanavalin A (costimulation- dependent mitogen) or phorbol 12-myristate 13-acetate and ionomycin (costimulation independent mitogens) alone or in the presence of (hu)CTLA4-Ig, cyclosporine, or dexamethasone; effects of these treatments on lymphocyte proliferation were assessed by incorporation of thymidine labeled with tritium or flow cytometry. Antigen-specific proliferation was determined by stimulating PBMCs from 2 healthy cats seropositive for Toxoplasma gondii with soluble Toxoplasma antigen alone or in the presence of (hu)CTLA4-Ig or cyclosporine.

Results—(hu)CTLA4-Ig inhibited costimulationdependent lymphocyte proliferation in vitro but had no effect on costimulation-independent lymphocyte proliferation. Compared with mitogen alone, (hu)CTLA4-Ig caused a significant decrease in responder frequency and proliferative capacity of CD4+ T cells; however, the effect on CD8+ T cells was not significant. Cyclosporine alone or with dexamethasone had a significantly greater suppressive effect on responder frequency and proliferative capacity of CD4+ and CD8+ T cells, compared with (hu)CTLA4-Ig. Compared with cyclosporine, (hu)CTLA4-Ig appeared to have a sparing effect on antigen-specific proliferation of memory CD4+ and CD8+ T cells.

Conclusions and Clinical Relevance—(hu)CTLA4-Ig selectively inhibited costimulation-dependent proliferation of lymphocytes in vitro and had a sparing effect on antigen-specific proliferation of memory cells. The specificity of its mechanism of action suggests that (hu)CTLA4-Ig may prevent allograft rejection but leave memory responses to previously encountered antigens intact. (Am J Vet Res 2005;66:483–492)

Abstract

Objective—To determine whether human CTLA4-Ig ([hu]CTLA4-Ig) inhibits costimulation-dependent lymphocyte proliferation in vitro, compare the effects of (hu)CTLA4-Ig with cyclosporine and steroids on CD4+ and CD8+ T-cell lymphocyte proliferation, and determine whether memory T-cell function remains intact in the presence of (hu)CTLA4-Ig.

Animals—29 cats.

Procedure—Peripheral blood mononuclear cells (PBMCs) were stimulated with concanavalin A (costimulation- dependent mitogen) or phorbol 12-myristate 13-acetate and ionomycin (costimulation independent mitogens) alone or in the presence of (hu)CTLA4-Ig, cyclosporine, or dexamethasone; effects of these treatments on lymphocyte proliferation were assessed by incorporation of thymidine labeled with tritium or flow cytometry. Antigen-specific proliferation was determined by stimulating PBMCs from 2 healthy cats seropositive for Toxoplasma gondii with soluble Toxoplasma antigen alone or in the presence of (hu)CTLA4-Ig or cyclosporine.

Results—(hu)CTLA4-Ig inhibited costimulationdependent lymphocyte proliferation in vitro but had no effect on costimulation-independent lymphocyte proliferation. Compared with mitogen alone, (hu)CTLA4-Ig caused a significant decrease in responder frequency and proliferative capacity of CD4+ T cells; however, the effect on CD8+ T cells was not significant. Cyclosporine alone or with dexamethasone had a significantly greater suppressive effect on responder frequency and proliferative capacity of CD4+ and CD8+ T cells, compared with (hu)CTLA4-Ig. Compared with cyclosporine, (hu)CTLA4-Ig appeared to have a sparing effect on antigen-specific proliferation of memory CD4+ and CD8+ T cells.

Conclusions and Clinical Relevance—(hu)CTLA4-Ig selectively inhibited costimulation-dependent proliferation of lymphocytes in vitro and had a sparing effect on antigen-specific proliferation of memory cells. The specificity of its mechanism of action suggests that (hu)CTLA4-Ig may prevent allograft rejection but leave memory responses to previously encountered antigens intact. (Am J Vet Res 2005;66:483–492)