Achieving incompatible transplantation through desensitization: current perspectives and future directions

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Date: Apr. 2015
From: Immunotherapy(Vol. 7, Issue 4)
Publisher: Future Medicine Ltd.
Document Type: Report
Length: 12,825 words
Lexile Measure: 1780L

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Author(s): Stanley C Jordan [*] aff1 aff2 aff3 , Jua Choi aff1 , Ashley Vo aff1

Keywords:

B cells; complement inhibition; desensitization; HLA; IL-6 receptor; immunotherapy; IVIg; kidney transplantation; plasma exchange; rituximab

Despite advances in immunologic assessment of allograft recipients, improvements in clinical care and immunosuppressive medications, the long-term outcomes for renal allografts remains unacceptably low [ 1-3 ]. Causes for the accelerated decline of allografts is multifactorial, but recent data indicate a reversal of the long held thesis that calcineurin inhibitor toxicity was responsible for the majority of chronic allograft failures [1,2 ]. It is now recognized that alloimmune responses both overt and clandestine are responsible for the majority of allograft failures which total 5000 per year in the US [3 ]. The cost associated with failed allografts with return to dialysis represents a considerable financial burden to the health care system while decreasing the length and quality of life of those affected. Thus, it is imperative that relevant pathological pathways responsible for allograft loss be identified with subsequent development of therapeutic interventions aimed at them. With this approach, there is a reasonable expectation for improvement in the duration and quality of allograft function. Today, this represents one of the most important and potentially achievable goals of transplant medicine.

Renal transplantation is considered the treatment of choice for end stage renal disease [4,5 ], however, rates of transplantation are low for patients with high levels of preformed anti-HLA antibodies [6 ]. HLA sensitized patients (HS) exhibit an immunologic barrier to transplantation that is linked to an increased risk of antibody-mediated rejection (ABMR), poor graft survival [6,7 ] and imposes a major immunologic deterrent to transplantation. Approximately 30% of the patients on the kidney transplant waiting list have evidence of sensitization to HLA manifest as alloantibodies generated through previous exposures to transplants, blood transfusions and pregnancy. Approximately 6.5% of patients with HLA panel-reactive antibody (PRA) levels above 80% receive a transplant each year. Over the past decade, attempts to improve transplant rates and outcomes among this difficult group have emerged. These protocols are loosely referred to as desensitization protocols combining B lymphocyte-depleting agents (rituximab, anti-CD20) [4 ], intravenous immunoglobulin (IVIg) and plasmapheresis [8-11 ]. Evolution of this process has occurred in concert with better alloantibody detection techniques that led to better stratification of immunological risk using sensitive donor-specific HLA antibody (DSA)-screening and avoidance techniques and use of desensitization with paired donor exchange to improve rates of transplantation for sensitized patients. Despite reports of improved short-term graft survival, the impact of these strategies is unclear, since ABMR continues as a major issue, occurring in 30-40% cases. This remains the primary cause of early graft loss after desensitization. In addition, transplant glomerulopathy is a known consequence of persistent DSA positivity which rapidly degrades allograft function resulting in graft failure and return to dialysis with attendant emotional consequences for the patients and their families [12-19 ]. Here, we will discuss outcomes of current desensitization protocols and new advances emerging from therapies aimed at treating autoimmunity and malignant...

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Gale Document Number: GALE|A411322522