Abstract

Remarkable progress of the past four decades in organ recovery, preservation and transplantation techniques, as well as in the management of immune therapy have allowed achieving reproducibly long-term survival of transplanted tissues. However, chronic immunosuppression remains one of the major challenges of organ transplantation due to the untowards side effects such as organ toxicity, increased risk of opportunistic infections and neoplasms. Multiple strategies are being evaluated to induce immune tolerance to transplanted tissues and promote long-lasting graft function, while avoiding the burden of anti-rejection therapy in transplant recipients. In fact, immune tolerance has been considered the Holy Grail of transplant immunobiology.

The clinical feasibility of achieving indefinite acceptance of transplanted organs after discontinuation of anti-rejection drugs originally comes from the observation that several patients who mantained graft survival after weaning chronic immunosuppression for a number of reasons (that is, not necessarily by protocol design). The seminal discovery that the ‘tolerant’ organ transplant recipients displayed persistance of donor mononuclear cells migrating from the transplanted organ(s) to the hosts’ tissues (a phenomenon defined as ‘microchimerism’) ¹ , ² , ³ , ⁴ prompted exciting research endeavors that led the discovery of the importance of donor dendritic cell (DC) chimerism on graft outcome ⁵ , ⁶ , ⁷ , ⁸, and to subsequent clinical trials with high doses of donor-specific hematopoietic stem cell inocula (i.e., obtained from vertebral body marrow) ⁹ , ¹⁰ to enhance solid and cellular transplantation outcomes in the last two decades ¹¹ , ¹² , ¹³ , ¹⁴ , ¹⁵ , ¹⁶ , ¹⁷, ¹⁸ , ¹⁹ , ²⁰ , ²¹ , ²² , ²³ , ²⁴ , ²⁵ , ²⁶ , ²⁷. Only recently, long term acceptance of allogenic solid organ transplantation has been reported in the clinical setting following lympho-ablative protocols combined with donor hematopoietic cell transplantation to induce chimerism and weaning of immunosuppression by design in small cohorts of patients ²⁸ , ²⁹ , ³⁰ , ³¹ , ³² , ³³ , ³⁴. Development of predictive molecular and functional markers ³⁵ , ³⁶ , ³⁷, ³⁸ , ³⁹ , ⁴⁰ , ⁴¹ , ⁴² , ⁴³ , ⁴⁴ , ⁴⁵ may assist in discriminating between responders and nonresponders to therapies aimed at promoting immune tolerance allowing for higher degrees of success more reproducibly in future clinical trials.

We feature in the ‘Back to the Future’ section of the current issue of CellR4 a manuscript entitled “Induction of Pancreatic Islet Graft Acceptance: The Role of Antigen Presenting Cells” by Camillo Ricordi, Suzanne T. Ildstad and Thomas E. Starzl published in Transplantation Science 1992 in which it was proposed that Antigen Presenting Cells (APC) may exert immunomodulatory functions able to promote immune tolerance in the context of organ transplantation ⁴⁶. The full text of the manuscript is available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3092700/.

In hindsight, contextualized in the historical timeframe, the working hypothesis of a ‘tolerogenic’ DC had to be considered quite unconventional when it was put forth. Indeed, the putative function of DC was considered to be pro-inflammatory APC in the early 1990’s ⁴⁷ , ⁴⁸, and therefore interventions aimed at modulating the immune system to promote self-tolerance (in the case of autoimmunity) and donor-specific transplant tolerance (in the case of cellular or solid organ grafts) were rather focused on their deletion ⁴⁹ , ⁵⁰ , ⁵¹.

The idea that APC could play an active role in the promotion of immune tolerance stemmed from the original observation by the Authors that donor DC repopulation of the host’s bone marrow was associated with the induction of operational tolerance in full chimeric animals receiving islet xenografts without the need for chronic immunosuppression ⁵² , ⁵³ , ⁵⁴ , ⁵⁵. Thus, they recognized a potential dual role of APC in the context of allograft and xenograft rejection and/or tolerance induction, suggesting the novel concept that “APCs may play an active role in graft acceptance” ⁵⁶.

Fast-forward to the present time, the scientific community by and large has widely accepted that tolerogenic APC play a critical role in maintaining the homeostasis of the immune system. In recent years, significant research endeavors helped dissecting out the fascinating role of tolerogenic APC and the associated complex immune network interactions, while also exploring strategies aimed at harnessing these properties to promote regulatory immune circuits in the context of autoimmunity, allergy and transplantation ⁵⁷ , ⁵⁸ administered under a non-myeolblative low-intensity conditioning protocol ⁵⁹ , ⁶⁰. In light of the encouraging results of these clinical trials, it was appropriate to select the manuscript by Drs. Ricordi, Ildstad and Starzl ⁶¹ for this issue’s “Back to the Future”, since the initial observations and innovative concept proposed in their manuscript may sound prophetic today, having paved the way for the steady progress of cellular-based therapies to induce transplant tolerance in the clinical arena.

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