How Regenerative Medicine May Contribute to the Achievement of an Immunosuppression-Free State (2011)

We read with interest the review article on clinical operational tolerance (COT) after solid organ transplantation by Bishop et al. (1). While we agree that there has been great progress in the pursuit of COT, it is important to point out that—based on the available information (2–4)—it may only be possible to achieve COT in a well-selected subset of liver graft recipients and in exceptional circumstances after renal transplantation. Unfortunately, all other types of solid organ transplants are not suitable for the implementation of tolerogenic or immunosuppression (IS) weaning strategies. However, now that significant progress in regenerative medicine has been made (5, 6), it may be time to consider combining both immunology- and regenerative medicine-based approaches to achieve COT. In fact, we believe that the harnessing of the immunomodulatory capabilities of stem cells with their ability for tissue repair and regeneration provides a stimulating opportunity for further research in the field of solid organ transplantation with the potential to address the two major issues of modern transplantation, namely COT and the search for a new, potentially inexhaustible source of graft. It is incontrovertible that well-selected liver transplant recipients may be weaned off IS at some point after transplantation (2). These individuals do not require any additional treatment to become tolerant and, even if they develop acute rejection during the weaning process, they are not exposed to an increased risk for graft loss once IS is resumed compared with recipients who do not reject. The overall safety of the IS weaning process in appropriately selected liver transplant patients renders weaning attempts ethically acceptable given the benefits derived from a long-term IS-free state. On the other hand, it is equally incontrovertible that recipients of grafts other than livers are more refractory to IS weaning (3). Very few renal transplant recipients have been intentionally weaned off IS, mainly following the onset of life-threatening complications such as malignancy, infection, or IS-related toxicity late after transplantation, which ultimately justified the attempt of weaning. The rare cases in which presumed so-called tolerogenic regimens have been administered to renal failure patients who received a kidney graft and hematopoietic stem cells from the same donors have shown in general the inadequacy of such an approach and the lack of safety of IS weaning in this setting (3, 4). As a corollary, it should be noted that at present so-called tolerogenic strategies or molecules or cells do not really exist, based on the available data. Regenerative medicine has recently shown the potential to meet the two major needs of transplantation, namely the identification of a new, theoretically inexhaustible source of organs and COT. Vessels, bladders, segments of upper airways, and urethras have been bioengineered from autologous cells and successfully implanted in patients suffering from different diseases without the need for IS (Table 1) (5). For the first time in cases not involving identical twins, the implanted tissues were well accepted by the immune system of the recipient without the need for any IS. These “transplants” were accomplished with an immediate, stable and durable IS-free state, which was made possible by the autologous origin of the bioengineered constructs.TABLE 1: Reported cases of implantation of bioengineered tissues (5,6)TABLE 1: ContinuedThe above-mentioned bioengineered tissues were hollow organs, which are relatively simple from an anatomic and physiologic perspective, compared with more composite complex modular organs, namely, organs organized in functioning units referred to as modules and requiring the reconstruction of the vascular supply (5, 6). However, heart, liver, and lung organoids have been recently engineered from animal organs that were decellularized and repopulated with organ-specific cells (5, 6). Surprisingly, such organoids were able to reproduce some of the functions of their innate full counterparts. As we speak, investigators are also trying to bioengineer segments of the digestive tract, pancreata, and kidneys (6), while others are pursuing the same objectives through a developmental biology- or stem cell-based approach (5–7). Importantly, a segment of porcine intestine has been decellularized and repopulated with autologous cells that were harvested and expanded from a patient suffering from a major tracheoesophageal defect (8). The so-obtained construct was eventually implanted in the forearm of the same patient to investigate whether the new organ would remain viable in view of a possible implantation to replace the diseased body part. Overall, history-making progress in hollow organ bioengineering may be opening a new era for the transplant field (5, 6, 9). The regenerative medicine platform may offer an alternative and valuable approach in the pursuit of COT with a number of theoretical advantages. Primarily, the recipient of a bioengineered tissue will probably never need any IS during follow-up. Secondarily, as the new organs are custom made, they may be manufactured and implanted in a timely manner according to a patient's general condition. Giuseppe Orlando1,2 Kathryn J. Wood3 Shay Soker1 Robert J. Stratta2 1Wake Forest Institute for Regenerative Medicine Department of Health Sciences Wake Forest Baptist Health Winston-Salem, NC 2Section of Transplantation Department of General Surgery Wake Forest University School of Medicine Winston-Salem, NC 3Transplantation Research Immunology Group Nuffield Department of Surgical Sciences University of Oxford Oxford, United Kingdom