CTLA4IG INHIBITS ALLOANTIBODY RESPONSES TO REPEATED BLOOD-TRANSFUSIONS

Allosensitization is a fundamental problem that limits the effectivene ss of blood transfusions. Patients who receive multiple transfusions o f blood or blood components frequently develop alloantibodies against donor alloantigens. Allosensitized patients are refractory to further transfusion and difficult to transplant successfully. CTLA4Ig fusion p rotein, which blocks the CD28-B7 costimulatory pathway in T-lymphocyte activation, was tested for its capacity to inhibit allosensitization to blood transfusions. Groups of LEW (RT1(l)) rats were transfused wit h ACI blood (RT1(a)) together with L6 (a human immunoglobulin G1 [IgG1 ] antibody as isotype control) or CTLA4Ig in different doses (0.004, 0 .02, 0.1, and 0.5 mg). Rats were retransfused with ACI blood after 28 and 84 days without any additional CTLA4Ig therapy. Weekly sera sample s were tested for alloantibody against donor leukocytes using flow cyt ometry. CTLA4Ig caused a dose-dependent decrease in the IgM alloantibo dy response against donor major histocompatibility complex (MHC) class I antigens. In addition, 0.02-, 0.1-, and 0.50-mg doses of CTLA4Ig to tally inhibited the IgG responses to the first transfusion, and this i mmunosuppressive effect persisted for the second and third transfusion s. To study the capacity of CTLA4Ig to prevent a secondary immune resp onse, three groups of LEW rats were transfused with ACI blood with no accompanying treatment. Animals were retransfused 28 days later with A CI blood together with L6 control antibody or 0.5 or 2.5 mg CTLA4Ig. C TLA4Ig, but not L6, prevented an increase in IgG alloantibody response despite repeated transfusions. The effects of CTLA4Ig treatment on he lper T-lymphocyte proliferation was tested by limiting dilution analys is (LDA). Peripheral blood cells taken 30 days after blood transfusion and CTLA4Ig treatment contained significantly decreased donor-specifi c T-lymphocyte precursors compared with L6-treated rats. These data su pport the idea that blocking the B7/CD28 signal of T-lymphocyte activa tion by CTLA4Ig treatment at the time of transfusion may be an importa nt therapeutic tool to inhibit alloantibody responses to blood transfu sions. (C) 1996 by The American Society of Hematology.