Desensitization for solid organ and hematopoietic stem cell transplantation

Abstract

Desensitization protocols are being used worldwide to enable kidney transplantation across immunologic barriers, i.e. antibody to donor HLA or ABO antigens, which were once thought to be absolute contraindications to transplantation. Desensitization protocols are also being applied to permit transplantation of HLA mismatched hematopoietic stem cells to patients with antibody to donor HLA, to enhance the opportunity for transplantation of non-renal organs, and to treat antibody-mediated rejection. Although desensitization for organ transplantation carries an increased risk of antibody-mediated rejection, ultimately these transplants extend and enhance the quality of life for solid organ recipients, and desensitization that permits transplantation of hematopoietic stem cells is life saving for patients with limited donor options. Complex patient factors and variability in treatment protocols have made it difficult to identify, precisely, the mechanisms underlying the downregulation of donor-specific antibodies. The mechanisms underlying desensitization may differ among the various protocols in use, although there are likely to be some common features. However, it is likely that desensitization achieves a sort of immune detente by first reducing the immunologic barrier and then by creating an environment in which an autoregulatory process restricts the immune response to the allograft.

Treatment of donor-specific antibody-mediated graft rejection by immunochemotherapy, third-party DLI, plasmapheresis and immunoadsorption

“…Therefore, the patient received a highdose i.v.IG (1 g/kg bodyweight) on day +33, followed by extracorporeal DSA elimination using plasmapheresis (exchange of 1, 5 plasma volumes against fresh frozen plasma) on days +34 and +35 (MFI 9538 before the first and MFI 6581 after last plasmapheresis). We observed a transient decrease in the DSA titers after each treatment, which was rapidly followed by a rebound of antibody titers the following day -a well-described phenomenon 2 (Supplementary Table S1). …”

“…Most prophylactic desensitization protocols used irradiated lymphocyte infusions (DLI) or platelet infusions from the original donor or infusion of surrogate platelets. 2 In our patient, no DLI or donor platelets were available, as this donor was prepared for the second donation. In this special situation, we took advantage of the fact that the haploidentical son carried the same mismatched A2 antigen as the donor (Table 1).…”

Donor HLA-specific Abs: to BMT or not to BMT?

“…9,15,20–24 The key requirement appears to be sufficient reduction of DSA to prevent Ab-mediated destruction of donor cells before they can engraft. Among the different desensitization regimens, combinations of PP with rituximab and/or IVIG have been most often used and have demonstrated successful DSA reduction.…”

“…9,15,20–24 Protocols have included adsorption of Abs on Staphylococcus protein A columns or with donor platelets; treatment with the proteasome inhibitor bortezomib; and various combinations of plasmapheresis (PP) with i.v. Ig (IVIG) and/or the anti-CD20 monoclonal Ab, rituximab (reviewed in Zachary and Leffell 24 ). The majority of these reports have been anecdotal, including from one to four cases, but taken together have indicated that reduction of DSA to low levels can permit successful engraftment.…”

Critical updates in the 7th edition of the American Society for Apheresis guidelines

“…Many therapies have been utilized to negate the effect of HLA antibodies on the graft due to increased incidence of graft failure in recipients with HLA DSAs. These therapies include TPE, IA, IVIG, tacrolimus, mycophenolate mofetil, rituximab, and bortezomib …”