Harnessing Mechanisms of Immune Tolerance to Improve Outcomes in Solid Organ Transplantation: A Review

Abstract

Survival after solid organ transplantation (SOT) is limited by chronic rejection as well as the need for lifelong immunosuppression and its associated toxicities. Several preclinical and clinical studies have tested methods designed to induce transplantation tolerance without lifelong immune suppression. The limited success of these strategies has led to the development of clinical protocols that combine SOT with other approaches, such as allogeneic hematopoietic stem cell transplantation (HSCT). HSCT prior to SOT facilitates engraftment of donor cells that can drive immune tolerance. Recent innovations in graft manipulation strategies and post-HSCT immune therapy provide further advances in promoting tolerance and improving clinical outcomes. In this review, we discuss conventional and unconventional immunological mechanisms underlying the development of immune tolerance in SOT recipients and how they can inform clinical advances. Specifically, we review the most recent mechanistic studies elucidating which immune regulatory cells dampen cytotoxic immune reactivity while fostering a tolerogenic environment. We further discuss how this understanding of regulatory cells can shape graft engineering and other therapeutic strategies to improve long-term outcomes for patients receiving HSCT and SOT.

Biomaterial Strategies for Selective Immune Tolerance: Advances and Gaps

“…[28][29][30][31] Delivered systemically, mTOR inhibitors broadly suppress immune responses, which has made these drugs components of the life-long management transplant recipients undergo to minimize or slow rejection. [32,33] In models of autoimmunity, delivering these drugs in a material modified the effect of mTOR inhibitors from broad suppression to antigen-specific tolerance. In some cases, delivery of mTOR inhibitors alone using material strategies has been used to treat autoimmunity and autoinflammation without broad suppression.…”

Epidemiology of Invasive Fungal Infections in Solid Organ Transplant Recipients: an Indian Perspective

“…The development of IFI in SOT is primarily governed by the balance between the host characteristics including immune status, and exposure to the prevalent fungi in the environment [ 26 , 27 ]. The host factors like prior colonization with the fungal agent, a breach in mucosal barriers, co-morbid conditions like diabetes, malnutrition, cirrhosis, etc.…”

Tolerogenic Nano-/Microparticle Vaccines for Immunotherapy

“…More targeted remedies include the use of recombinant cytokines and monoclonal antibodies (mAbs), for instance, adalimumab (cytokine depletion antibody) and rituximab (B cell depletion antibody). − These treatments are more specific compared to the conventional ones, but they do not have selectivity since they bind their target receptors displayed on all healthy and abnormal cells . Therefore, they could cause harmful effects to normal cell function. ,, The cell-based strategies, which include adoptive immunotherapy and stem cell transplantation to inhibit autoreactive T cells and restore immune tolerance, face manufacturing, purification, and scale-up challenges to realize their full potential. , Moreover, current therapies often require lifelong, repeated, and even daily administration and are not curative. , Besides, the induced tolerance usually has insufficient coverage and requires the periphery regulation provided by specific antigen-presenting cells (APCs) on T cells. , Altogether, these drawbacks of existing treatments highlight the importance of engineering safer, more effective, and long-term approaches inducing more selective immune tolerance.…”