Scientific Report 2007

Molecular and Experimental Medicine

Division of Blood Cell and Vascular Biology

Regulation of Allogeneic Immune Responses to Cell Transplants

L. Crisa, R. Prinsen, V. Cirulli,* B.E. Torbett

* Whittier Institute, La Jolla, California

Class I and class II MHC antigens are the primary barrier to acceptance of allografts. However, certain class I MHC antigens may also trigger regulatory immune responses. Thus, in humans, HLA-G, a nonpolymorphic class Ib HLA molecule, may mediate immunologic tolerance at sites of immune privilege, such as the anterior chamber of the eye, the testis, the thymus, and the cytotrophoblast.

Several explanations for the immunoregulatory functions of HLA-G have been considered. The limited polymorphism of HLA-G in humans may allow the recognition of tissues expressing high levels of this molecule as "self," thereby preventing the activation of autoreactive or alloreactive T cells and natural killer cells. Alternatively, HLA-G may foster the development of specific immunoregulatory lymphocytes capable of downregulating alloreactivity. Our previous finding that HLA-G is expressed in the thymic medullary epithelium in humans strongly supports both possibilities. Thus, the purpose of HLA-G expression in the thymic medulla may be to both (1) educate developing T cells to recognize HLA-G as self and (2) induce the selection of HLA-G–specific immunoregulatory T-cell populations.

We are investigating the immune responses elicited by HLA-G in human thymocytes and peripheral T cells. Our goals are to dissect the molecular mechanisms of HLA-G immune functions and then use this information to bioengineer HLA-G expression in tissues suitable for transplantation. Particular emphasis is given to models of pancreatic islet transplantation for the treatment of diabetes. For this purpose, we have generated lines of human pancreatic cells expressing either low or high levels of membrane-bound or soluble recombinant HLA-G. These HLA-G^low and HLA-G^high cell lines are useful tools for studies of HLA-G functions both in vitro and in vivo in models of cell transplantation.

Another promising line of research for the bioengineering of cells for transplantation was provided by our work on the identification of endothelial cell progenitors in human cord blood. While studying human thymopoiesis in a chimeric mouse model in which mice are reconstituted with human cord blood, we discovered that cord blood hematopoietic stem cells engrafted in these mice not only reconstituted the bone marrow and repopulated the human thymic grafts but also contributed to the formation of new blood vessels at sites of wound healing.

We are characterizing this population of putative endothelial progenitors to be used as another target cell type for transplantation. Specifically, we have defined some of the growth and differentiation signals required for the expansion ex vivo of human bone marrow–derived endothelial progenitors. Currently, using a mouse model of bone marrow–derived vasculogenesis, we are characterizing immunologic and angiogenic properties of bone marrow–derived endothelium. Ultimately, cotransplanting HLA-G–transduced allogeneic tissue along with HLA-G–bioengineered endothelial cell progenitors and/or enhancing recruitment of bone marrow–derived endothelium with intrinsic immunomodulatory properties may endow tissue grafts with an additional level of immunoprotection. This approach may be useful in developing novel strategies for the induction of immunologic tolerance and/or the avoidance of rejection after transplantation.