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


METHODS
29 cats.


METHODS
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 costimulation-dependent 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
(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.
Aronson
Lillian R
LR
Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104-6010, USA.
Drobatz
Kenneth J
KJ
Hunter
Christopher A
CA
Mason
Nicola
N
D000069594:Abatacept; D000818:Animals; D000953:Antigens, Protozoan / Q000494:pharmacology*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects*; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects*; D002415:Cats / Q000276:immunology*; D049109:Cell Proliferation / Q000187:drug effects; D003208:Concanavalin A / Q000494:pharmacology; D016572:Cyclosporine / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D005434:Flow Cytometry / Q000662:veterinary; D018796:Immunoconjugates / Q000276:immunology / Q000494:pharmacology*; D007156:Immunologic Memory / Q000187:drug effects / Q000276:immunology; D007165:Immunosuppression Therapy / Q000379:methods*; D015759:Ionomycin / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014122:Toxoplasma
D000953:Antigens, Protozoan; D018796:Immunoconjugates; D003208:Concanavalin A; D015759:Ionomycin; D000069594:Abatacept; D003907:Dexamethasone; D016572:Cyclosporine; D013755:Tetradecanoylphorbol Acetate