Dominant immune response to HLA-B57/B58 molecules after platelet transfusion.

BACKGROUND: Patients with hematologic malignancies require prophylactic or curative platelet transfusions to prevent or treat bleeding. Treatments such as chemotherapy, radiotherapy, and hematopoietic stem cell transplantation cause persistent thrombocytopenia, necessitating platelet transfusions. However, class I HLA antibodies can cause a serious complication: immune-mediated platelet refractoriness. The mechanisms of alloimmunization are incompletely understood. We explored the immunogenicity of HLA molecules and the phenotype of the HLA-specific CD4+ T cells involved in alloimmunization. STUDY DESIGN AND METHODS: We investigated the role of HLA molecules in platelet transfusion immunogenicity in a retrospective cohort study on men with specific anti-HLA who had undergone transfusion. We investigated the presence and phenotypic profile of HLA-specific CD4+ T cells in alloimmunized patients included in long-term platelet transfusion programs for hematologic malignancies. RESULTS: More than 50% of the transfused subjects displayed an antibody response against HLA-B57 or -B58. HLA-B57-specific CD4+ T-cell responses were observed in patients alloimmunized against HLA-B57. Following specific stimulation, the patients presented HLA-specific CD4+ T cells producing tumor necrosis factor-α, interleukin (IL)-13, IL-17A, IL-2, IL-10, and IL-21. CONCLUSION: These results shed light on posttransfusion class I anti-HLA alloimmunization mechanisms and constitute a first step toward developing new strategies for reducing refractoriness.

Immune interactions and regulation with CD39+ extracellular vesicles from platelet concentrates.

Introduction: CD39 plays an important role in the immunoregulation and inhibition of effector cells. It is expressed on immune cells, including Tregs, and on extracellular vesicles (EVs) budding from the plasma membrane. Platelet transfusion may induce alloimmunization against HLA-I antigens, leading to refractoriness to platelet transfusion with severe consequences for patients. Tregs may play a key role in determining whether alloimmunization occurs in patients with hematologic disorders. We hypothesized that CD39+ EVs might play an immunoregulatory role, particularly in the context of platelet transfusions in patients with hematologic disorders. Such alloimmunization leads to the production of alloantibodies and is sensitive to the regulatory action of CD39. Methods: We characterized CD39+ EVs in platelet concentrates by flow cytometry. The absolute numbers and cellular origins of CD39+ EVs were evaluated. We also performed functional tests to evaluate interactions with immune cells and their functions. Results: We found that CD39+ EVs from platelet concentrates had an inhibitory phenotype that could be transferred to the immune cells with which they interacted: CD4+ and CD8+ T lymphocytes (TLs), dendritic cells, monocytes, and B lymphocytes (BLs). Moreover, the concentration of CD39+ EVs in platelet concentrates varied and was very high in 10% of concentrates. The number of these EVs present was determinant for EV-cell interactions. Finally, functional interactions were observed with BLs, CD4+ TLs and CD39+ EVs for immunoglobulin production and lymphoproliferation, with potential implications for the immunological management of patients.

Immunoregulatory molecule expression on extracellular microvesicles in people living with HIV.

Introduction: People living with HIV (PLWH) now benefit from combined antiviral treatments that durably control viral replication. These antiretroviral treatments decrease mortality and improve quality of life in PLWH, but do not completely control the excessive non-specific activation of the immune system in PLWH. This chronic immune activation is a key element of HIV immunopathology that contributes to the pathophysiology of inflammatory comorbid conditions, such as cardiovascular disorders, cancer and autoimmune diseases. Circulating non-exosomal extracellular vesicles, also known as microparticles (MPs) are detected in these diseases and have been linked to immune activation. The objective of this study was to characterize the MPs present in PLWH and to assess their association with chronic immune activation. Methods: We performed flow cytometry for the complete phenotypic characterization of MPs from fresh plasma from PLWH and from people without HIV as the control group. The absolute number, size and cellular origin of MPs were evaluated. The immunoregulatory profile was determined by cell origin, for MPs derived from platelets (PMPs), monocytes (MMPs) and T lymphocytes (LMPs). Results: PLWH had significantly more circulating MPs than controls, for MPs of all sizes originating from T lymphocytes, red blood cells, neutrophils, dendritic cells, B lymphocytes and endothelial cells. PMPs and MMPs were not more numerous in PLWH, but the immunoregulatory phenotypes of these MPs differed between PLWH and controls. These differences in immunoregulatory molecule expression profile were also observed for LMPs. PDL1, ICOSL, CCR5, TGFß1, MHC classes I and II, TRAIL, CXCR4, OX40, DC-SIGN, CTLA4 and PDL2 were more strongly expressed on the surface of MPs from PLWH than on those from controls. Conclusion: MPs are an important element in intercellular communication, making it possible to transfer phenotypes and functions to immune cells. The significantly higher numbers of MPs expressing diverse immunomodulatory molecules in PLWH may make a major contribution to the maintenance and/or the development of immune-cell activation in these individuals.