Commentary

Sirolimus and ciclosporin for renal transplantation

Myasthenia Gravis (MG) is an autoimmune disease caused by complement-fixing antibodies against the acetylcholine receptors (AChR). Antigen-specific CD4 + T cells, Tregs and Th17 + are also necessary. Consequently, antibodies, B cells, molecules associated with signalling pathways on T helper cells, cytokines and complement are targets for more specific treatment options.

Because available immunosuppressive therapies cause unacceptable side effects after long-term use or are not always effective in inducing remission, novel biological agents directed against the following targets might be options for future therapies in MG: 1) T cell Intracellular Signaling Pathways associated with T cell activation, such as monoclonal antibodies against CD52, Interleukin 2-receptor (IL-2 R), co-stimulatory molecules or compounds inhibiting Janus tyrosine kinases JAK1, JAK3; 2) B cells, against key B cell-surface molecules or trophic factors B cell activation factor (BAFF) and a proliferating inducing ligand (APRIL); 3) Complement, against C3 or C5 that intercept membranolytic attack complex formation; 4) Cytokines and cytokine receptors, including IL-6, IL-17, the p40 subunit of IL12/1L-23, and GM-CSF; and 5) Lymphocyte migration molecules. Construction of recombinant AChR antibodies that block the binding of the pathogenic antibodies, can be a future molecular tool.

New biological agents are in the offing for future therapies in MG. Their efficacy needs to be secured with vigorously controlled clinical trials and weighted against excessive cost and rare complications.

Late kidney allograft failure remains a major problem in kidney transplantation. While there is no doubt that acute nephrotoxicity from calcineurin inhibitors (CNIs) exists, chronic CNI nephrotoxicity has been the subject of much debate in the transplant community.

We identified original articles related to the use of CNIs in renal and extra-renal solid-organ transplantation, to examine the available evidence about their chronic nephrotoxicity.

There is clearly a lack of firm evidence for the role of CNIs as a major injurious agent causing chronic renal dysfunction and allograft failure. Moreover, recent evidence shows that the pathological lesions typically linked to chronic CNI use are not specific. A growing body of evidence shows that alloimmunity is a much more important cause of late renal allograft failure.

More research should focus on addressing the true causes of chronic graft dysfunction rather than continuing to propagate the exaggerated contribution of CNIs to late graft loss.

Sirolimus (SRL) and everolimus are members of a relatively new class of immunosuppressants that impair cell cycle proliferation by inhibition of the mammalian target of rapamycin. These agents have been evaluated and licensed for use in kidney transplantation where they are used predominantly as maintenance immunosuppression because they lack the nephrotoxicity associated with calcineurin inhibitors. Neither SRL nor its newer analogue everolimus are currently licensed for use in liver transplantation, but both have been used with varying degrees of success and efficacy in this setting. Concern has been expressed about a potential association between de novo use of SRL and both a high incidence of hepatic artery thrombosis after liver transplantation and impaired wound healing, and thus, subsequent development has focused on the use of SRL in response to calcineurin inhibitor toxicity in patients with established liver transplants as well as using its potential antitumor effects in patients transplanted for malignancy. This article reviews the reported experience of mammalian target of rapamycin inhibitor therapy in liver transplantation.