CTLA4Ig inhibits alloantibody responses to repeated blood transfusions
S Ibrahim, F Jakobs, D Kittur, A Hess, PS Linsley, F Sanfilippo and WM Baldwin
Department of Pathology, The Johns Hopkins University School of Medicine,
Baltimore, MD 21205, USA.
Allosensitization is a fundamental problem that limits the effectiveness of
blood transfusions. Patients who receive multiple transfusions of blood or
blood components frequently develop alloantibodies against donor
alloantigens. Allosensitized patients are refractory to further transfusion
and difficult to transplant successfully. CTLA4Ig fusion protein, 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') rats were transfused with ACI blood (RT1a) 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 samples were tested for alloantibody against
donor leukocytes using flow cytometry. CTLA4Ig caused a dose- dependent
decrease in the IgM alloantibody response against donor major
histocompatibility complex (MHC) class I antigens. In addition, 0.02-,
0.1-, and 0.50-mg doses of CTLA4Ig totally inhibited the IgG responses to
the first transfusion, and this immunosuppressive effect persisted for the
second and third transfusions. To study the capacity of CTLA4Ig to prevent
a secondary immune response, three groups of LEW rats were transfused with
ACI blood with no accompanying treatment. Animals were retransfused 28 days
later with ACI blood together with L6 control antibody or 0.5 or 2.5 mg
CTLA4Ig. CTLA4Ig, but not L6, prevented an increase in IgG alloantibody
response despite repeated transfusions. The effects of CTLA4Ig treatment on
helper T-lymphocyte proliferation was tested by limiting dilution analysis
(LDA). Peripheral blood cells taken 30 days after blood transfusion and
CTLA4Ig treatment contained significantly decreased donor-specific
T-lymphocyte precursors compared with L6-treated rats. These data support
the idea that blocking the B7/CD28 signal of T-lymphocyte activation by
CTLA4Ig treatment at the time of transfusion may be an important
therapeutic tool to inhibit alloantibody responses to blood transfusions.
Volume 88,
Issue 12,
pp. 4594-4600,
12/15/1996
Copyright © 1996 by The American Society of Hematology
