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

Abstract

Summary. 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 b 2 -microglobulin-specific antibody, protected against alloantibody production to five subsequent untreated platelet challenges. Use of complement fixing, non-fixing or F(ab H ) 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/Fcg receptor) or murine IgG and was thus independent of B-cell FcgRII-mediated immune suppression. The inhibition observed was independent of HLA alloantigenic specificity as antibodies directed at the b 2 -microglobulin portion of HLA class I were as effective as antibodies against any of the HLA-a 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 FcgRII-mediated immune regulation, complement fixing or HLA alloantigenic specificity.

Antibody-Mediated Immune Suppression of Erythrocyte Alloimmunization Can Occur Independently from Red Cell Clearance or Epitope Masking in a Murine Model

“…The Ab response to RBCs can be downregulated by the simultaneous administration of an RBC-specific Ab concurrent with exposure to the foreign red cell (1)(2)(3)(4). This effect has been termed Ab-mediated immune suppression (AMIS), and AMIS has been observed with a variety of different cell types, including platelets, leukocytes, microbes, and particulate Ags, such as vaccines in different mammals (5)(6)(7)(8).…”

Immunoglobulin G‐mediated regulation of the murine immune response to transfused red blood cells occurs in the absence of active immune suppression: implications for the mechanism of action of anti‐D in the prevention of haemolytic disease of the fetus and newborn?

“…In support of this, we have previously shown in a model of alloimmunity to MHC that anti-MHC antibodies can prevent the antibody response as well as the T-cell response against allogeneic MHC under the conditions studied. 17,39 The findings presented here further suggest that IgGmediated antigen clearance is, in itself, also not the sole mechanism of AMIS. Both in the presence and absence of specific IgG, SRBC are rapidly cleared from the circulation.…”

“…9,13 Nonetheless, it does not appear to be necessary for all the epitopes of the antigen to be blocked to prevent the antibody response. Furthermore, the effect of IgG does not appear to be epitope specific 8,9,[14][15][16][17] and the therapeutic amount of anti-RBC antibody that prevents the antibody response in mice does not saturate all the epitopes on foreign RBCs. 18 Similarly, monoclonal anti-D antibodies that covered only 20% of D antigen sites on D-positive RBCs successfully prevented the antibody response to D antigen.…”

Does Rh immune globulin suppress HLA sensitization in pregnancy?

“…Some animal experiments suggest that IgG Fc is required for AMIS, 25 while other experiments suggest that Fc is dispensable. 14,26 Even the question of whether AMIS is truly antigen-specific remains controversial. In 1968, Pollack and colleagues 27 reported the results of several AMIS experiments in a rabbit model.…”