Benefits, efficacy, cost-effectiveness and infectious complications in transplant patients desensitized with intravenous immunoglobulin and anti-CD20 therapy.

Renal transplantation is the treatment of choice for end-stage renal disease (ESRD), as it offers improved quality of life and survival 1–3. Currently, there are more than 100 000 ESRD patients on the deceased donor (DD) waiting list and almost 30 000 new patients register annually, yet only 16 895 kidney transplants were performed in 2013 [Organ Procurement and Transplantation Network (OPTN) data as of August 2014] 3. Unfortunately, the growing number of patients waiting for kidney transplants exceeds our ability to provide this life-saving treatment. This is particularly true for patients who are difficult to match due to human leukocyte antigen (HLA)-specific alloantibodies (resulting from previous pregnancies, blood or blood transfusions and transplantations). The recognition of the importance of alloantibodies and B cells as mediators of acute and chronic allograft injury is not new, but the magnitude of the problem is now well recognized 4. B cells and alloantibodies were felt to be important (but less important than T cells) as mediators of allograft injury. The deleterious effects of antibodies to HLA antigens that result from exposure to human tissues or blood are well known and prohibitive to transplantation. Patients who receive transplants across these incompatibilities show hyperacute rejection with rapid loss of graft function 4. Therefore, the presence of donor-specific anti-HLA antibodies (DSA) is considered a contraindication to transplantation 4,5. Sensitization to HLA antigens is long-lived and associated with memory B cells and plasma cells. Without modification, the opportunities for transplantation are minimal 6. Because of this, desensitization protocols have emerged using therapies directed at antibodies and B cells 6–13. These therapies have dramatically increased the rates of transplantation for this immunologically disadvantaged population. Of additional importance is the recognition of distinct and separate pathways that facilitate antibody-mediated rejection (AMR), which is a devastating consequence of DSA production after transplantation, with a more chronic form, transplant glomerulopathy, now recognized as a probable consequence of long-term exposure to DSA 14–17. Thus, alloantibody and allospecific B cells have emerged as major pathogenic factors for prevention of successful transplantation and a major cause for the decreased half-life of kidney transplants 18,19. B cells probably contribute to the pathogenesis of T cell-mediated rejection (CMR) and AMR through multiple pathways. B cells play a key role in presenting antigen to CD4+ T cells in collaboration with dendritic cells and other antigen-presenting cells (APC) 20–23. B cells express a number of co-stimulatory molecules (B7, CD40) that aid in co-stimulation of activated T cells and in their progression to full effector and cytotoxic functions. This is, of course, in addition to the role of B cells and plasma cells in producing DSA that has the capacity to activate complement and induce antibody-dependent cellular cytotoxicity (ADCC). B cells also produce a number of cytokines that are proinflammatory and promote cell injury directly or through activation of cytotoxic effector cells. B effector cells produce proinflammatory cytokines such as lymphotoxin-α, interferon (IFN)-γ and interleukin (IL)-6 21–23. IL-6 was identified as a critical B cell cytokine responsible for relapse of multiple sclerosis 24. In this study, patients treated with B cell depletion with rituximab showed elimination of IL-6-producing B cells and developed remission from disease. IFN-γ-producing B cells have been identified in active systemic lupus erythematosus (SLE) and are felt responsible for increased T helper type 1 (Th1) cytokine production with concomitant reductions in regulatory T cells (Tregs). In addition, B regulatory subsets also exist, and have the capacity to modify inflammation and autoimmunity in animal models 20. In an effort to optimize the availability of compatible donors, several transplant centers have developed desensitization protocols aimed at modification of alloantibodies and B cells to reduce HLA sensitization and AMR. There are two widely accepted desensitization protocols: low-dose intravenous immunoglobulin with plasma exchange (IVIg/PLEX) and high-dose IVIg (HD-IVIg). IVIg/PLEX has been used successfully in ABO-incompatible and in positive cross-match (+CMX) renal transplantation 8,9, while HD-IVIg has been used to desensitize both living-donor +CMX and highly sensitized (HS) DD recipients on the waiting list 6,7,10–13. HD-IVIg (2 g/kg) in multiple-dosing regimens is considered a reasonable approach for desensitization 25. The B cell-depleting agent, rituximab, is used frequently in combination with HD-IVIg and IVIg/PLEX protocols 8–12. Experience with the IVIg/rituximab protocol has shown that rituximab has a critical role in modifying alloreactive B cells and prevention of DSA rebound 26,27. Here, we will discuss data regarding the safety, efficacy and economic aspects of current desensitization protocols.