News and Publications

Integrins and Chemokines in Structure-Function Models of Cell Transplantation

D.R. Salomon, L. Crisa, J.K. Ishii, L. van der Laan, B. Griffeth, B.E. Torbett,* K. Smith,* B. Beuhler,* H. Perkins,* A. Pelletier,** A. Hayek,*** G. Beatty***

* Department of Immunology, TSRI
** Department of Cell Biology, TSRI
*** University of California, San Diego, CA

Our major theme is that the structural elements of tissue compartments are important determinants of tissue function. One corollary is that the transition between health and disease involves loss of tissue structure, leading to disordered function. It follows that successful cell transplantation requires mechanisms, including angiogenesis, to protect or facilitate development of normal tissue structure.

THYMIC DEVELOPMENT

We study the mechanisms that regulate movement of human thymocytes from bone marrow to thymus; between the developmental compartments, the medulla and cortex, in the thymus; and from the thymus to the periphery. Our studies elucidate the role of integrin adhesion molecules and examine regulated forms of adhesion and migration, the compartment-specific expression of integrin ligands, the relationship between developmental stage and expression of chemokine receptors, and the compartment-specific expression of chemokines.

PANCREATIC ISLET CELL TRANSPLANTATION

Our structure-function approach suggested that transplantation of pancreatic islet cells can fail because islet structure is not protected. We are now testing organ cultures created in 3-dimensional templates designed with a library of cyclic peptide analogs based on integrin adhesive sequences. These templates can protect islet structure and enhance angiogenesis, 2 critical determinants of successful engraftment. Studies include transplanting human or pig islets into mouse and nonhuman primate models, because a workable strategy for xenotransplantation is the only practical solution for 1.4 million patients in the United States who have insulin-dependent diabetes mellitus.

BONE MARROW AND THYMIC TRANSPLANTATION

Our studies of the movement of progenitor cells are supported by models of human stem cell and thymic transplantation in immunodeficient mice, which we have used to create an in vivo program of hematopoietic and thymic development. We are now investigating the role of a novel form of angiogenesis mediated by bone marrow--derived cells that may also be relevant to islet transplantation. We recently advanced a novel model of human graft-vs-host disease to test T cell--based gene therapies for cancer or for induction of tolerance.

CELL MIGRATION AND DIRECTION

Chemokines mediate cell migration via a novel family of receptors. However, little is known of the intracellular signal connections or biological mechanisms. We focused on stromal derived factor 1 (SDF-1), which is produced by cells in the bone marrow that express vascular cell adhesion molecule-1. We showed that SDF-1 is also produced by the cortical epithelial cells in the thymus that express vascular cell adhesion molecule-1. We also showed expression of SDF-1 receptors by T-cell progenitors. This mechanistic link between cell development in the bone marrow and thymus is logical and relevant to our model studies. Most recently, we concentrated on how SDF-1 can signal and regulate T-cell migration via integrins. These studies suggest new models for how T cells can follow a ligand or chemokine gradient creating directional migration (Fig. 1).

PUBLICATIONS

The Banff Author Group The Banff 97 Working Classification of Renal Allograft Pathology. Kidney Int., in press.

Brunson, M.E., Salomon, D.R. Prophylaxis and treatment of renal transplant rejection. In: Principles of Nephrology. Johnson, R., Freehally, J. (Eds.). Mosby International, London, in press.

Colvin, R.B., Cohen, A.H., Saiontz, C., Bonsib, S., Buick, M., Burke, B., Carter, S., Cavallo, T., Haas, M., Lindblad, A., Manivel, J.C., Nast, C.C., Salomon, D.R., Weaver, C., Weiss, M. Evaluation of pathological criteria for acute renal allograft rejection: Reproducibility, sensitivity and clnical correlation. J. Am. Soc. Nephrol. 8:1930, 1997.

Crisa, L., Cirulli, V., Smith, K.A., Ellisman, M.H., Torbett, B.E., Salomon, D.R. Human cord blood progenitors sustain thymic T-cell development and a novel form of angiogenesis. J. Clin. Invest., in press.

Salomon, D.R. The molecular basis of transplantation immunity. In: Kidney Transplant Rejection, 3rd ed. Racusen, L.C., et al. (Eds.). Marcel Dekker, New York, 1998, p.1.

Zaitseva, M.B., Mojcik, C.F., Salomon, D.R., Shevach, E.M., Golding, H. Co-ligation of ₄ß₁ integrin and TCR rescues human thymocytes from steroid-induced apoptosis. Int. Immunol., in press.