In previous posts,we described general approaches to tackle allo- and autorejection. However, we cannot assume that all stem cell-based therapies will have the same requirements in terms of making them accepted by the recipient, inasmuch as different stem cell types may have different immunological properties. Embryonic stem cells, for instance, have been recently claimed to be “immunoprivileged,” following a series of in vitro and in vivo experiments where both human embryonic stem (huES) cells and their differentiated progeny failed to elicit substantive immune responses. The authors hypothesized that this effect was due to the lack of major histocompatibility class II molecules in the surface of the cell, although it is well known that rejection will invariably occur if class I molecules are present. From this perspective, success at evading the immune response is more likely to come from stem cell banking, which would ensure an appropriate representation of the most widely spread HLA haplotypes in the population. Even more interesting is the recent progress at generating HLA homozygous huES cell lines by means of parthenogenesis of which one carries the most commonly found (and shared by different racial groups) HLA haplotype in the US population. This strategy is very promising, but HLA homology would not be sufficient to prevent secondary rejection mechanisms. The only way we could ensure that huES cells do not trigger an immune response in the recipient is by tailoring them by means of somatic cell nuclear transfer or induced pluripotent stem (iPS) cell generation . Unfortunately, the former technology is not available yet for humans, and it would probably be impractical from a logistic point of view. As for the latter, there are still enormous safety concerns related to the use of retroviruses to reprogram patient-derived somatic cells.
Adult stem cells, on the contrary, could be easily derived from the patient and expanded in vitro prior to re-differentiation and implantation. As would be the case with patient-derived huES/iPS cells, this approach would theoretically circumvent the immune rejection of the tissue. In both cases, however, the problem of autoimmunity would still require additional interventions. The use of mesenchymal stem cells (MSCs) in an allotransplantation setting has also been proposed based on the observation that these cells have immunomodulatory properties. The hypothesis was that these cells might be able to engraft even in allogeneic recipients, down-regulating the immune response. However, this theory has been proven incorrect in a number of in vivo experiments and now the prevailing view is that the effects of MSCs in mismatched settings might be due to transient trophic/secretory effects. Some argue that a solution to the autoimmunity component of type I diabetes might be just enough to cure the disease. After all, it has been observed that insulin-positive cells persist even decades after the onset of the disease, suggesting that regeneration mechanisms are at play throughout the course of the disease, but perhaps kept at bay by the autoimmune response. It is likely, however, that regeneration will not be possible unless a critical mass of beta cells remains in the pancreas.This would explain why the “reeducation” of the immune system proposed by Voltarelli et al. was not hypothesized to work in patients with long-standing diabetes. Therefore, a boost of exogenous cells will be required even after the autoimmunity problem has been solved. The jury is still out regarding whether this second component of the cure (replacement) will come from embryonic stem cells, adult stem cells, transdifferentiation, or regeneration. It might also be the case that success is the result of a combination of several approaches. A theoretical clinical intervention, for instance, may involve the differentiation of huES cells into both pancreatic endocrine tissue and hematopoietic cells with the ability to induce chimerism – and tolerance – in any given patient. Provided that concerns about teratomas are conveniently addressed, the stem cells could thus be used both as a replacement and a tolerance inducing tool . The same approach would be applicable to a situation where hematopoietic cells (bone marrow or cord blood) are differentiated into beta cells and co-transplanted with undifferentiated aliquots for tolerance induction. In a different setting, we cannot entirely rule out the possibility that some forms of transdifferentiation may result in the generation of insulin-producing cells that, not being true beta cells, may actually be in a better position to evade the immune response. Finally, the use of MSCs is likely to help in virtually any therapeutic intervention by virtue of their immunomodulatory and “feeder” effects. The bottom line is that the several strategies presented in previous chapters, far from being exclusive of each other, are expected to work in a synergistic fashion; and that the knowledge gathered from each field will certainly cross-fertilize the others. The themes herein discussed are so new and rapidly evolving that this book could not have been written a decade ago. We can only hope that, 10 years from now, all of these novel concepts will have finally settled and the field will have advanced much closer to a definitive cure for type I diabetes.
ES cells homozygous for the most widely represented HLA haplotypes can be generated by means of parthenogenesis. This process is the result of the fusion of a haploid egg with an haploid polar body generated during the maturation of the former.
Theoretical co-transplantation of hematopoietic and pancreatic beta cells derived from a single universal huES cell donor.
Tags: differentiation of huES cells, Embryonic Stem Cells, ES cells homozygous, hematopoietic cells, HLA haplotypes, HLA homology, immunological properties, pancreatic endocrine tissue, pluripotent stem (iPS) cell generation, single universal huES cell donor, theoretical clinical intervention, Theoretical co-transplantation of hematopoietic and pancreatic beta cells