Monoclonal antibody-mediated inhibition of the human HLA alloimmune response to platelet transfusion is antigen specific and independent of Fcγ receptor-mediated immune suppression

Presensitization of donor platelets with allospecific immunoglobulin (Ig)G results in a diminished immune response against subsequent transfusions of platelets. To understand better the mechanism of how alloantibody presensitization results in a decreased alloimmune response, we have used murine monoclonal antibodies directed to polymorphic and non-polymorphic regions of human leucocyte antigen (HLA) as well as platelet-specific molecules. Here, we demonstrated that presensitization with anti-human HLA class I antibodies, as well as beta(2)-microglobulin-specific antibody, protected against alloantibody production to five subsequent untreated platelet challenges. Use of complement fixing, non-fixing or F(ab')(2) fragments of HLA-specific antibody also resulted in complete inhibition of alloantibody production. This protection was not seen when the platelets were presensitized with monoclonal antibodies to CD42a (GPIX), CD32 (low-affinity IgG/Fc gamma receptor) or murine IgG and was thus independent of B-cell Fc gamma RII-mediated immune suppression. The inhibition observed was independent of HLA alloantigenic specificity as antibodies directed at the beta(2)-microglobulin portion of HLA class I were as effective as antibodies against any of the HLA-alpha regions (either polymorphic or nonpolymorphic) of class I. This work demonstrates that monoclonal antibody-mediated suppression of the human HLA alloimmune response to platelet transfusion is antigen specific and is independent of Fc gamma RII-mediated immune regulation, complement fixing or HLA alloantigenic specificity.