Novel Strategies in Immunosuppression: Issues in Perspective

Abstract

Recent findings suggest that a chronic alloimmune response is playing the dominant role in late allograft loss, challenging the notion that most grafts are lost due to the inexorable progression of calcineurin inhibitor (CNI) nephrotoxicity. CNIs have failed to improve long-term outcomes and are associated with multiple metabolic derangements. Thus, improvement in long-term allograft outcomes may depend on new agents with novel mechanisms of action, devoid of the toxicities associated with CNIs. To meet this need, inhibitors of novel pathways in B cell and plasma cell activation have emerged to combat the humoral immune response including belimumab and atacicept, both promising targets of B-cell survival factors and bortezomib and eculizumab, agents currently in trials for desensitization protocols and treatment of antibody-mediated rejection. Promising agents for maintenance immunosuppression, used as monotherapy or synergistically, include monoclonal antibodies and fusion receptor proteins targeting the CD40-CD154 pathway (multiple anti-CD40 antibodies), the CD28-CD80/86 pathway (i.e., belatacept), the LFA3-CD2 pathway (i.e., alefacept), and small molecules such as tofacitinib, a janus kinase 1/3 inhibitor. The induction of allograft tolerance has been attempted with some success with simultaneous bone marrow/kidney transplantation from the same donor, albeit, limited by its associated toxicites. Finally, the exciting fields of tissue engineering and stem cell biology with the repopulation of decellularized organs is ushering in a new paradigm for transplantation. The era of simplified immunosuppression regimens devoid of toxicities is upon us with the promise of dramatic improvement in long term survival.

Local Tissue Geometry Determines Contractile Force Generation of Engineered Muscle Networks

“…The use of angiogenic and/or neurotrophic factors, 7,30 electrical and mechanical stimulation, 9,16,31 and coculture with vascular and/or neuronal cells 6,32,33 are just some of the potential strategies to achieve this goal. Development of improved immunosuppression regimes 34 and cell sources with robust regenerative capacity (e.g., from human pluripotent stem cells 35 ) are some of the other important milestones toward the therapeutic use of tissue engineering to restore lost muscle function.…”

Development of a Sensitive Phospho-p70 S6 Kinase ELISA to Quantify mTOR Proliferation Signal Inhibition

“…1 The proliferation signal inhibitor rapamycin (ie, sirolimus and its derivative everolimus) provides appropriate immunosuppression without significant nephrotoxicity. 2 In addition, sirolimus-based calcineurin inhibitor-free therapy is associated with a decreased incidence of de novo malignancies.…”

Böbrek Naklinde Kullanılan Yeni İmmünsupresif İlaçlar

“…Kompleman C5 proteinine bağlanarak C5 konvertaz ile C5a ve C5b'ye yıkımını önleyerek membran atak kompleksi oluşumunu engeller ve kompleman aracılı hücre hasarına engel olur (1). Eculizumab temelde terminal kompleman kaskadını hedefler, ancak proksimal kompleman yolaklarının etkisini ortadan kaldıramayabilir.…”