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FcγRIII blockade prevents anti-HLA-mediated platelet clearance in a humanized murine model of platelet transfusion
Lazaro Gil Gonzalez1, Kevin Doyoon Won1,2, Zoya Tawhidi1,3,4
1Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Unity Health Toronto, Toronto, ON, Canada.
Immune platelet transfusion refractoriness (iPTR) is a major complication in transfusion medicine. Although anti-HLA antibodies are recognized contributors, the mechanisms by which they drive platelet clearance remain incompletely defined. We examined sera from 18 patients with iPTR and found that anti-HLA antibodies induced uptake of human platelets expressing the cognate HLA-A2 target antigen and platelet particles derived from these platelets. These sera also mediated clearance of transgenic mouse platelets expressing human HLA-A2. Using THP-1-CD16A macrophages, uptake of both platelets and platelet particles was mediated predominantly through FcγRIIIa, with a partial contribution from FcγRI and little to no role for FcγRII. To test this pathway in vivo, we used a reductionist humanized murine model of iPTR in which HLA-A2 transgenic mouse platelets sensitized with human iPTR sera were transfused into FcγR-humanized mice. In this model, FcγRIII blockade with 17C02-albumin prevented platelet clearance under the conditions tested. These findings extend previous FcγR studies in antibody-mediated platelet clearance to the alloimmune setting of iPTR and support further investigation of FcγRIII-dependent pathways in antibody-mediated PTR.
Immune platelet transfusion refractoriness (iPTR) is a major complication in transfusion medicine. Although anti-HLA antibodies are recognized contributors, the mechanisms by which they drive platelet clearance remain incompletely defined. We examined sera from 18 patients with iPTR and found that anti-HLA antibodies induced uptake of human platelets expressing the cognate HLA-A2 target antigen and platelet particles derived from these platelets. These sera also mediated clearance of transgenic mouse platelets expressing human HLA-A2. Using THP-1-CD16A macrophages, uptake of both platelets and platelet particles was mediated predominantly through FcγRIIIa, with a partial contribution from FcγRI and little to no role for FcγRII. To test this pathway in vivo, we used a reductionist humanized murine model of iPTR in which HLA-A2 transgenic mouse platelets sensitized with human iPTR sera were transfused into FcγR-humanized mice. In this model, FcγRIII blockade with 17C02-albumin prevented platelet clearance under the conditions tested. These findings extend previous FcγR studies in antibody-mediated platelet clearance to the alloimmune setting of iPTR and support further investigation of FcγRIII-dependent pathways in antibody-mediated PTR.
