Surrogate beta cells


(most notably the Diabetes Control and Complications Trial) have proven that normalization of blood glucose will prevent the onset and progress of diabetic complications. Islet cell transplantation seems the obvious way to achieve normalization of blood glucose in patients with both insulin-dependent (IDDM) and non-insulin-dependent (NIDDM) diabetes mellitus, but there are several major obstacles to be overcome. The obstacles fall into two broad categories. First is the category of immunologic rejection. Since the adverse effects of non-selective immunosupressive regimens are unacceptable for an otherwise healthy diabetic patient, solutions must be found that specifically abrogate transplant rejection. If human cells are the donor source, this means overcoming the allorejection mechanism, which is currently thought to be mediated primarily by CD8 + cytotoxic lymphocytes which recognize specific antigens associated with beta-cell class I MHC molecules, “dock” with these targets, and stimulate destruction of the graft cells. If animal cells are the donor source, this means overcoming the mechanisms of xenorejection, which involve an immediate, hyperacute rejection phase that destroys the graft in hours, caused by preexisting xenoreactive natural antibodies that bind primarily to a single saccharide epitope (Gal alpha 1–3Gal) which is present on most animal tissues but is absent in man. Binding of antibody activates complement proteins in the patient’s blood which bind to and destroy the graft. After the hyperacute phase of xenorejection, there is a chronic cell-mediated phase that appears to involve CD4 + effector cells producing low molecular weight toxic products such as cytokines and reactive oxygen species. Although specific inhibition of either allograft rejection or xenograft rejection would allow cure of non-autoimmune NIDDM, it is less certain that this would be sufficient for curing autoimmune IDDM. In IDDM patients, the problem of recurrent autoimmune destruction will also have to be addressed. Over the past few years, exciting advances have been made towards the solution of these problems. Approaches to rejection and autoimmune destruction aim either 1) to modify the recipient’s immune system, or 2) to modify the donor graft tissue. Approaches to modifying the recipient’s immune system include a) creation of full or mixed chimerism, using temporary immunosupression plus donor bone marrow; b) implantation of islets into the thymus with transient immunsupression; and c) systemic administration of co-stimulator antagonists, which block the allogeneic T-cell activation that is dependent on ligation of T-cell CD28 with APC B7, and/or CD40 with gp39. Approaches to modifying donor graft tissue include for allorejection a) genetic engineering of graft tissue to express fas ligand [fasL], which lyses fasbearing activated T cells on contact: and b) down regulation of MHC class I by genetic engineering; for the hyperacute phase of xenorejection, a) the expression of the human complement inhibitors daf and cd59 on transgenic organs; and b) the expression in transgenic organs of a competitive inhibitor of Gal alpha1–3 Gal, fucosyltransferase. For the cellular phase of xenorejection, and perhaps for recurrent autoimmunity as well, antiapoptosis genes such as bcl-2 have been shown to protect beta cells against cytokine-induced cell death. Lastly, immunoisolation of graft tissue Diabetologia (1997) 40: B39–B43

DOI: 10.1007/BF03168185

Cite this paper

@article{Ferber1997SurrogateBC, title={Surrogate beta cells}, author={Sandy Ferber and Harry Heimberg and Michael D Brownlee and Cheryl Colton}, journal={Diabetologia}, year={1997}, volume={40}, pages={B39-B43} }