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208. CTLA4-Ig Prevents Alloantibody Production and BMT Rejection in Response to Platelet Transfusions in Mice

Author

Gilson, Christopher R, Patel, Seema R, and Zimring, James C

Subjects
CD4-Positive T-Lymphocytes, Graft Rejection, Mice, Inbred BALB C, Immunoconjugates, Drug Evaluation, Preclinical, H-2 Antigens, Platelet Transfusion, Lymphocyte Activation, Adoptive Transfer, Article, Abatacept, Mice, Inbred C57BL, Mice, Graft Enhancement, Immunologic, Isoantibodies, Radiation Chimera, Animals, Female, Immunization, Leukocyte Reduction Procedures, Histocompatibility Antigen H-2D, Bone Marrow Transplantation
Abstract

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.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.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.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.

Published
2012

209. Initiation and Regulation of Complement during Hemolytic Transfusion Reactions

Author

Stowell, Sean R., Winkler, Anne M., Maier, Cheryl L., Arthur, C. Maridith, Smith, Nicole H., Girard-Pierce, Kathryn R., Cummings, Richard D., Zimring, James C., and Hendrickson, Jeanne E.

Subjects
Article Subject
Abstract

Hemolytic transfusion reactions represent one of the most common causes of transfusion-related mortality. Although many factors influence hemolytic transfusion reactions, complement activation represents one of the most common features associated with fatality. In this paper we will focus on the role of complement in initiating and regulating hemolytic transfusion reactions and will discuss potential strategies aimed at mitigating or favorably modulating complement during incompatible red blood cell transfusions.

Published
2012
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210. Alloimmunization to transfused platelets requires priming of CD4+ T cells in the splenic microenvironment in a murine model

Author

Gilson, Christopher R and Zimring, James C

Subjects
CD4-Positive T-Lymphocytes, Mice, Inbred C57BL, Isoantigens, Mice, Mice, Inbred BALB C, Isoantibodies, Models, Animal, Animals, Platelet Transfusion, Article, Spleen
Abstract

Alloantibodies are a clinically significant sequelae of platelet (PLT) transfusion, potentially rendering patients refractory to ongoing PLT transfusion support. These antibodies are often IgG class switched, suggesting the involvement of CD4+ T-cell help; however, PLT-specific CD4+ T cells have not been visualized in vivo, and specifics of their stimulation are not completely understood.A murine model of alloimmunization to transfused PLTs was developed to allow in vivo assessment and characterization of CD4+ T cells specific for PLT major histocompatibility complex (MHC) alloantigen. PLTs were harvested from BALB/c mice, filter leukoreduced, and transfused into C57BL/6 recipients. PLT-specific CD4+ T-cell responses were visualized by using a T-cell receptor transgenic mouse that detects peptide from donor MHC I presented on recipient MHC II. Antibody responses were determined by indirect immunofluorescence using BALB/c donor targets.C57BL/6 recipients of BALB/c leukoreduced PLT transfusions produced BALB/c antibodies, with proliferation of antigen-specific CD4+ T cells seen in the spleen but not lymph nodes or liver. Depletion of recipient CD4+ cells or splenectomy independently abrogated the alloantibody response.We report a novel model to study antigen-specific CD4+ T cells during alloimmunization to PLT transfusion. The presented data support a critical role for CD4+ T-cell help in the humoral response to PLT transfusion and establish the spleen as a required microenvironment for effective CD4+ T-cell priming against donor PLT-derived MHC I.

Published
2011

225. Metabolomics of ADSOL (AS-1) Red Blood Cell Storage

Author

Roback, John D., primary, Josephson, Cassandra D., additional, Waller, Edmund K., additional, Newman, James L., additional, Karatela, Sulaiman, additional, Uppal, Karan, additional, Jones, Dean P., additional, Zimring, James C., additional, and Dumont, Larry J., additional

Published
2014
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243. Alloantibodies to a paternally derived RBC KEL antigen lead to hemolytic disease of the fetus/newborn in a murine model

Author

Stowell, Sean R., primary, Henry, Kate L., additional, Smith, Nicole H., additional, Hudson, Krystalyn E., additional, Halverson, Greg R., additional, Park, Jaekeun C., additional, Bennett, Ashley M., additional, Girard-Pierce, Kathryn R., additional, Arthur, C. Maridith, additional, Bunting, Silvia T., additional, Zimring, James C., additional, and Hendrickson, Jeanne E., additional

Published
2013
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