CTLA4-Ig prevents alloantibody production and BMT rejection in response to platelet transfusions in mice.
BACKGROUND
Platelet (PLT) transfusions can induce humoral and cellular alloimmunity. HLA antibodies can render patients refractory to subsequent transfusion, and both alloantibodies and cellular alloimmunity can contribute to subsequent bone marrow transplant (BMT) rejection. Currently, there are no approved therapeutic interventions to prevent alloimmunization to PLT transfusions other than leukoreduction. Targeted blockade of T-cell costimulation has shown great promise in inhibiting alloimmunity in the setting of transplantation, but has not been explored in the context of PLT transfusion.


METHODS
We tested the hypothesis that the costimulatory blockade reagent CTLA4-Ig would prevent alloreactivity against major and minor alloantigens on transfused PLTs. BALB/c (H-2(d)) mice and C57BL/6 (H-2(b)) mice were used as PLT donors and transfusion recipients, respectively. Alloantibodies were measured by indirect immunofluorescence using BALB/c PLTs and splenocytes as targets. BMTs were carried out under reduced-intensity conditioning using BALB.B (H-2(b) ) donors and C57BL/6 (H-2(b)) recipients to model HLA-identical transplants. Experimental groups were given CTLA4-Ig (before or after PLT transfusion) with control groups receiving isotype-matched antibody.


RESULTS
CTLA4-Ig abrogated both humoral alloimmunization (H-2(d) antibodies) and transfusion-induced BMT rejection. Whereas a single dose of CTLA4-Ig at time of transfusion prevented alloimmunization to subsequent PLT transfusions, administration of CTLA4-Ig after initial PLT transfusion was ineffective. Delaying treatment until after PLT transfusion failed to prevent BMT rejection.


CONCLUSIONS
These findings demonstrate a novel strategy using an FDA-approved drug that has the potential to prevent the clinical sequelae of alloimmunization to PLT transfusions.
Center for Transfusion and Cellular Therapies, Department of Pathology and Laboratory Medicine, and the Aflac Cancer Center and Blood Disorders Service, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Christopher R
CR
Gilson
Seema R
SR
Patel
James C
JC
Zimring
D000069594:Abatacept; D019264:Adoptive Transfer; D000818:Animals; D016026:Bone Marrow Transplantation / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000637:transplantation; D004353:Drug Evaluation, Preclinical; D005260:Female; D006082:Graft Enhancement, Immunologic / Q000379:methods*; D006084:Graft Rejection / Q000517:prevention & control*; D006183:H-2 Antigens / Q000276:immunology*; D064532:Histocompatibility Antigen H-2D; D007114:Immunization; D018796:Immunoconjugates / Q000494:pharmacology / Q000627:therapeutic use*; D007518:Isoantibodies / Q000096:biosynthesis*; D047589:Leukocyte Reduction Procedures; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D017713:Platelet Transfusion; D011828:Radiation Chimera
D006183:H-2 Antigens; D064532:Histocompatibility Antigen H-2D; D018796:Immunoconjugates; D007518:Isoantibodies; D000069594:Abatacept