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Commentary for macroencapsulation protects against sensitization after allogeneic islet transplantation in rats.

The effect on the rejection response of introducing a microporous membrane to surround transplanted cells was first investigated thoroughly over 50 years ago by Glenn H. Algire (1907–1958). Choosing a membrane with a pore size that prevented cell migration but allowed transfer of nutrients and proteins was found to profoundly inhibit the response to allogeneic tumor, but did not alter the response to xenografted tumor. This seminal work appeared to have been forgotten 25 years later when sporadic attempts were made to use the same approach for protecting xenogeneic islet transplants in a variety of devices during the 1970s, mostly involving quasicommercial ventures without repeatable success. In 1984, a technique of microencapsulation which preserved islet viability was described and was shown to allow cure of experimental diabetes for several months in a rodent allogeneic islet transplantation model (1). The prospect of transplanting islet tissue without immunosuppression produced a “feeding frenzy” with the rapid setting up of several biotech companies dedicated to that goal, concentrating on allogeneic canine and murine islet transplantation models. Further success was obtained with a variety of membrane constructs, but again the striking results were in allogeneic models, whereas xenogeneic models were much less convincing, which is a shame because only xenotransplantation makes logistical sense for islet transplantation. Most of the work on encapsulation in the late 1980s and early 1990s was performed under rules of commercial confidentiality that did not encourage open discussion or criticism, and the amount of work done to identify the underlying mechanisms was small compared to the millions spent searching for the most effective encapsulation membrane. Meanwhile, an advance in our understanding of the mechanisms of transplant rejection was underway with the definition of the key role of migratory dendritic cells and the recognition that not only could intact allo-major histocompatibility complex (MHC) molecules drive a direct immune response from T-cells, but also the peptides derived from allo-MHC could be presented by host antigenpresenting cells (APCs). This became known as the indirect pathway, whereas it should perhaps more correctly be called the normal pathway, as this is probably the usual route for detection of invader derived peptides. Subsequent investigation also identified the indirect pathway as the main route to detect the huge number of foreign peptides that drive the response to xenogeneic tissue. When the several concepts just presented above were applied to encapsulation of islets several points became obvious: firstly, a major effect of encapsulation would be to prevent migration of dendritic cells into the lymphoid tissue and therefore prevent direct MHC presentation. Secondly, the indirect pathway could be primed by protein antigen that was able to pass through the membrane pores, which could account for the intractable rejection of encapsulated xenografts. Both of these concepts now have considerable evidence to back them as being operativeinencapsulationpathophysiology.Thesefindingsforceda revision of the conceptual terminology relating to encapsulation from “immunoisolation” to “immunomodulation.” There are still important questions regarding the mechanism of the protection which encapsulation gives to allogeneic tissue and this is addressed by the study from Sorenby et al. in this issue of Transplantation, in which they have demonstrated that the allogeneic rejection response is abrogated for encapsulated rats islets by a mechanism that avoids cellular sensitization or antibody production, while unencapsulated islets were rapidly rejected. By good fortune (or design?), the exact rat strain/allogeneic combination (Dark Agouti [DA] into Lewis [LEW]) used in the Sorenby study was used before for studies which examined indirect pathway presentation in depth (2). It was shown that at least three immunodominant peptides derived from DA MHC class 2 were bound and presented by LEW recipient MHC. T-cell activation resulted as evidenced by in vitro proliferation and administration of the peptides in vivo resulted in antibody production and cellular sensitization. So it seems pertinent to stand the question on its head and ask why then does the indirect pathway not operate for rejection of allogeneic islets after encapsulation? The experimental findings in the Sorenby study seemed to exclude an active mechanism such as regulatory cell formation. Several alternative explanations spring to mind. It could be that the limited number of peptides driving the indirect response requires Nuffield Department of Surgery, University of Oxford, John Radcliffe Hospital, Headington, Oxford, United Kingdom. Address correspondence to: Derek W.R. Gray, M.D., Nuffield Department of Surgery, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DU U.K. E-mail: derek.gray@nds.ox.ac.uk Received 27 February 2006. Accepted 5 April 2006. Copyright © 2006 by Lippincott Williams & Wilkins ISSN 0041-1337/06/8203-310 DOI: 10.1097/01.tp.0000228876.05633.7c