Minimizing Immunosuppression, an Alternative Approach to Reducing Side Effects

Abstract

Exceptionally low acute rejection rates and excellent graft survival can be achieved with cyclosporine and tacrolimus (CNI)-based immunosuppressive protocols that incorporate antiproliferative immunosuppressants and corticosteroids. However, despite short-term success, long-term attrition of graft function and side effects of immunosuppressive agents continue to be significant problems, leaving clinicians looking for possible interventions. CNI nephrotoxicity is but one of numerous factors that may contribute to long-term damage in transplant kidneys. Metabolic, cosmetic, and neuropsychiatric complications of steroids affect quality of life after transplantation. Newer immunosuppressive agents such as mycophenolate mofetil and sirolimus (Rapa) have raised the possibility of withdrawing or avoiding CNIs or steroids altogether. In this report we review studies that address either CNI or steroid minimization strategies and discuss their risks versus benefits. Given the accumulated experience to date, in our opinion the use of CNIs and steroids as part of immunosuppressive regimens remains the proven standard of care for renal transplant patients. The long-term safety and efficacy of CNI and steroid minimization strategies needs to be further validated in controlled clinical trials with adequate long-term follow-up.

Calcineurin Inhibitor Nephrotoxicity

“…These approaches appear to be relatively safe (262,344,345), especially when mycophenolate mofetil is combined with tacrolimus, as was recently demonstrated in a large multicenter randomized trial in renal transplantation (222). By minimizing CNI levels, CNI nephrotoxicity might be partially avoided, but it has become clear that the increased risk of allograft rejection could annihilate these positive effects and even explain why the tacrolimus group has a better outcome than the other groups.…”

“…Briefly, it is obvious that complete avoidance of CNIs in immunosuppressive protocols will fully prevent the development of CNI nephrotoxicity. However, the exclusion of CNIs from the immunosuppressive regimens falls short of preserving allograft function due to inadequate acute rejection prophylaxis with the other immunosuppressive regimens (222,262,344,345). Therefore, CNI withdrawal may be a better option, through delivery of CNIs during the early high rejection risk period after transplantation followed by secondary conversion to less nephrotoxic agents, before significant irreversible renal damage occurs (344 -346).…”

Impact of irradiation and immunosuppressive agents on immune system homeostasis in rhesus macaques

“…Lastly, cohort 3 first underwent TBI then received anti-CD3 immunotoxin (CD3-IT) and a Janus activated kinase (JAK) inhibitor, both of which are newer therapies aimed at depleting T cells or inhibiting lymphocyte activation without the adverse effects sometimes associated with CNIs and other currently available drugs (reviewed in [18]). CD3-IT is a recombinant fusion protein consisting of a truncated diphtheria toxin fused to affinity matured anti-CD3 antibody FN18, which is able to deplete T cells [19].…”

A Simplified Immune Suppression Scheme Leads to Persistent Micro-dystrophin Expression in Duchenne Muscular Dystrophy Dogs

“…Immune-suppressive drugs, especially the T cell-depleting drugs, are associated with a broad range of side effects such as fever, headache, tremor, hematological abnormalities, liver and renal toxicity, and opportunistic infection (Srinivas and Meier-Kriesche, 2008;Gaber et al, 2010;Schonder et al, 2010). For these reasons, minimized immunosuppression has been strongly promoted in the field of organ transplantation (Vincenti, 2003).…”

“…1). This not only adds to the cost, but more importantly, it increases potential side effects (Srinivas and Meier-Kriesche, 2008;Gaber et al, 2010;Schonder et al, 2010).…”