Antibody-mediated Rejection In Transplant Recipients Research Articles

Marginal zone B cells are required for optimal humoral responses to allograft

Antibody-mediated rejection (AMR) is among the leading causes of graft failure in solid organ transplantation. However, AMR treatment options are limited by an incomplete understanding of the mechanisms underlying de novo donor-specific antibody (DSA) generation. The development of pathogenic isotype-switched DSA in response to transplanted allografts is typically attributed to follicular B cells undergoing germinal center reaction whereas the contribution of other B cell subsets has not been previously addressed. The current study investigated the role of recipient marginal zone B cells (MZ B cells) in DSA responses using mouse models of heart and renal allotransplantation. MZ B cells rapidly differentiate into antibody-secreting cells in response to allotransplantation. Despite the selective depletion of follicular B cells in heart allograft recipients, MZ B cells are sufficient for T-dependent IgM and early IgG DSA production. Furthermore, the presence of intact MZ B cell subset is required to support the generation of pathogenic isotype-switched DSA in renal allograft recipients containing donor-reactive memory helper T cells. These findings are the first demonstration of the role of MZ B cells in humoral alloimmune responses following solid organ transplantation and identify MZ B cells as a potential therapeutic target for minimizing de novo DSA production and AMR in transplant recipients.

A Model of Acute Antibody-Mediated Renal Allograft Rejection in the Sensitized Rata.

Antibody-mediated rejection in transplant recipients with preexisting donor-specific antibodies is a challenging clinical situation. However, we lack suitable animal models to study this scenario. The aim of this study was to develop an animal model of acute antibody-mediated rejection of renal allografts in sensitized recipients. We used major histocompatibility complex class I and II incompatible rat strains (Dark Agouti RT1av1 and Lewis RT1l), which develop aggressive rejection. Recipient Lewis rats were immunized with donor strain spleen cells 5 days before surgery to induce donor-specific antibodies. Rats underwent bilateral nephrectomy and orthotopic transplant of the donor kidney. To minimize T-cell-mediated rejection while allowing the development of donor-specific antibodies, recipient animals were given tacrolimus starting the day before surgery. Hyperacute rejection was not seen, but acute graft dysfunction was evident on day 1 with a rapid deterioration of graft function by day 3. Histologic damage featured glomerulopathy, capillaritis, capillary thrombosis, and acute tubular injury. Recipients exhibited high serum levels of donor-specific antibodies and deposition of immunoglobulin G and C4d on graft endothelium. Immunostaining showed substantial endothelial damage, fibrin deposition in glomerular and peritubular capillaries, and infiltrates of macrophages, neutrophils, and natural killer cells. T-cell activation was efficiently suppressed by tacrolimus. We have developed a clinically relevant model of acute antibody-mediated rejection in recipients with preexisting donor-specific antibodies, which is suitable for testing novel therapies.

Regulation of immunity and inflammation by intravenous immunoglobulin: relevance to solid organ transplantation

Intravenous immunoglobulin (IVIg) products are derived from pooled human plasma from thousands of donors and have been used for the treatment of primary immunodeficiency disorders for more than 30 years. IVIg products are also effective in the treatment of autoimmune and inflammatory disorders, however, the precise mechanism(s) of action are not known. Recent data suggest that IVIg has a much broader ability to regulate cellular immunity, including innate and adaptive components. IVIg-induced upregulation of Fcγ receptor IIB on B cells appears to be an important mode of action in suppression of antigen-presenting cell activity and antibody production. IVIg is also a recently recognized modifier of complement activation and injury. Analysis of clinical studies examining the use of IVIg in desensitization protocols and for treatment of antibody-mediated rejection in transplant recipients are supportive. Here, we discuss these important advancements and their relevance to transplant medicine.