Approaching the Promise of Operational Tolerance in Clinical Transplantation

Abstract

Long-term acceptance of transplanted organs without requirement for indefinite immunosuppression remains the ultimate goal of transplant clinicians and scientists. This clinical state of allograft acceptance termed "operational tolerance" has been elusive in routine practice. However, there are published reports of recipients where immunosuppression has been discontinued, by intention or patient noncompliance, in which the outcome is a nondestructive immune response and normal function. The question now arises how clinical operational tolerance might be achieved in the majority of recipients. This review provides an overview of current approaches to achieve operational tolerance, including the use of donor bone marrow and depletion of recipient T cells and the resistance of liver transplants to rejection. It also describes the key role of clinical immune monitoring and future approaches to tolerance induction including inhibition of T-cell signaling, manipulation of costimulatory pathways, and expansion of regulatory T cells. The principles of these experimental approaches may ultimately be extended to provide safe and effective control of transplant rejection and induction of clinical operational tolerance.

Acute cellular rejection in intra-abdominal solid organ allografts – immunology under the light microscope

“…Problems of immunologic injury and long-term complications of immunosuppression (including drug toxicity; neoplasms; and/or infections) however remain formidable, such that efforts in the last decade have concentrated on development of less toxic immunosuppressive agents and attempts to induce tolerance of the graft by the host immune system. 1,2 While positive steps have been recorded, this field continues to be both challenging in the quest to achieve true tolerance and exciting in terms of emerging knowledge. The surgical pathologist plays a critical role as a member of the clinical team managing these transplant patients.…”

Differences between buccal and lingual bone quality and quantity of peri-implant regions

“…While bone grafting is most commonly recommended to treat oral bone deficiency (Chen & Jin 2010, Mao, et al 2006, Pellegrini, et al 2009), its use is restricted due to significant limitations, which include donor site morbidity, risk of infection, inappropriate synthetic architecture, and post-implantation failures (Alpdogan & van den Brink 2012, Becktor, et al 2002, Bishop, et al 2011, Blanco, et al 2005, Brunel, et al 2001, Chen & Jin 2010, Delloye, et al 2007, Rios, et al 2011, Spin-Neto, et al 2013, Spin-Neto, et al 2014, Waasdorp & Reynolds 2010). Alternatively, many studies have observed that growth factors, including demineralized bone matrix (DBM) and bone morphogenetic proteins (BMP), successfully enhance oral bone augmentation (Gruskin, et al 2012, Higuchi, et al 1999, Kim, et al 2014, Wallace, et al 2014).…”

Clinical Immunosuppression

“…Safe, reliable strategies for the induction of full tolerance have not yet been developed [28]. However, during the study of achieving immune tolerance, methods to induce states of "partial tolerance" have been discovered; in these cases, lower-than-conventional amounts of ongoing pharmacologic immunosuppression are required to prevent rejection.…”