Mechanisms of Alloimmunization and Subsequent Bone Marrow Transplantation Rejection Induced by Platelet Transfusion in a Murine Model

Abstract

For many non-malignant hematological disorders, HLA-matched bone marrow transplantation (BMT) is curative. However, due to lack of neoplasia, the toxicity of stringent conditioning regimens is difficult to justify, and reduced-intensity conditioning is used. Unfortunately, current reduced-intensity regimens have high rates of BMT rejection. We have recently reported in a murine model that mHAs on transfused platelet products induce subsequent BMT rejection. Most non-malignant hematological disorders require transfusion support prior to BMT and the rate of BMT rejection in humans correlates to the number of transfusions given. Herein, we perform a mechanistic analysis of platelet transfusion induced BMT rejection and report that unlike exposure to alloantigens during transplantation, platelet transfusion primes alloimmunity but does not stimulate full effector function. Subsequent BMT is itself an additional and distinct immunizing event, which does not induce rejection without antecedent priming from transfusion. Both CD4+ and CD8+ T cells are required for priming during platelet transfusion, but only CD8+ T cells are required for BMT rejection. In neither case are antibodies required for rejection to occur.

Strategies to Inhibit Alloantibody Production in Alloprimed Murine Recipients of Hematopoietic Stem Cell Grafts

“…Our studies build upon previous work by others demonstrating that costimulatory signal deliver by helper T cells, predominantly transmitted via the indirect pathway of allorecognition, are required for induction of high titer, isotype switched, IgG, alloantibody reactive to donor antigens (7,8,10,(30)(31)(32)(33)(34)(35)(36). Using an allosensitization model in which the prior administration of a single fully MHC disparate splenocyte dose provides sufficient high-titer alloantibody to reject allogeneic BM grafts even 1 year postpriming, we newly demonstrate that only a combination of a highly depletionary anti-CD20 mAb plus LTbR-Ig that reduces GC formation sufficiently eliminates alloantibody to permit donor BM rescue of lethally irradiated, T-and NK-depleted recipients ( Figure 5D).…”

“…We and others have shown in preclinical murine models that allosensitization presents a formidable barrier to bone marrow (BM) engraftment (6)(7)(8)(9)(10)(11). Preformed alloreactive antibody, rather than primed donor reactive T cells, prevents engraftment of allogeneic full MHCdisparate BM in presensitized recipients: a single intravenous infusion of allogeneic splenocytes to mimic a blood transfusion resulted in high, sustained serum antibody titers sufficient to cause the elimination of a moderate dose of allogeneic BM in irradiated recipients by 3 h post-BMT (6).…”

Nephro and neurotoxicity of calcineurin inhibitors and mechanisms of rejections: A review on tacrolimus and cyclosporin in organ transplantation

“…Rejection can be defined as graft damage arising from response to the transplanted organ by the recipient immune system and may take several forms resulting in different clinical patterns (12)(13)(14). The two major presentations after liver transplantation are acute and chronic rejection, with hyperacute rejection rarely encountered (15,16).…”

“…Medawar was the first to assert that rejection was an immunological response, with the inflammatory reaction due to lymphocyte infiltration (1,9). Graft rejection may be governed in part by the type and extent of histocompatibility differences between donor and recipient with humoral mechanisms of likely greater importance in the rejection of renal than liver grafts (1,12,19). The two principal events of the human immune response are the recognition of epitopes on peptide antigens by T-cell receptors (TCR) and recognition of different epitopes on processed antigens by B-cell receptors.…”

Transfusion-Induced Bone Marrow Transplant Rejection Due to Minor Histocompatibility Antigens

“…Depletion of recipient CD4 + T cells after transfusions but prior to transplantation has been reported to prevent transfusion induced BMT rejection across mHA barriers [57]. On the contrary, CD4 + T cell depletion after rejection of an initial BMT but prior to rejection of a re-transplantation had no effect upon rejection of the second BMT [57].…”