Research Topics

CORNEAL ENDOTHELIAL CELL IMMUNOREGULATORY FACTORS

Summary

Principal Investigator: DALE SANNES GREGERSON
Abstract: DESCRIPTION (Adapted from applicant's abstract): Immune responses are important for protection from invading pathogens, but these responses have the potential to produce nonspecific injury in surrounding normal tissues. While many tissues tolerate nonspecific damage well and do not suffer permanent consequences, other sites such as the eye and brain, possess a delicate microanatomy whose integrity and function are easily damaged. It is known that these sites have developed the ability to modify immune responses to minimize inflammation and its consequences; i.e. they are immune privileged. Immune privilege was described long ago as the observation that allogeneic tissue grafts survive unusually well when placed in immune privileged sites, such as the anterior chamber of the eye, the brain, testis and placenta. For decades, immunologists were satisfied with the idea that the privilege solely resulted from immune ignorance due to the physical barriers between these antigens and the immune system. However, in the last 15 years, several active mechanisms have been described, indicating that ignorance of the antigens is not sufficienl The attention paid to the maintenance of immune privilege makes it clear that its biological significance is high, even though the mechanisms are still being elucidated. Both systemic and local effects have been implicated in maintaining the immune privilege of the eye. Previously, we reported that corneal endothelial (CE) cells inhibited antigen- and mitogen-activated lymphocyte proliferation assays, although lL-2R expression and responsiveness to exogenous 1L-2 were unaffected. To further examine this activity, co-cultures of CE cells and T cell clones were studied. CE cells selectively inhibited 1L-2 and 1L-4 production by T cells, but not 11-5 or 11-6 production. Preincubation of T cells with CE cells, or CE cell-conditioned culture supernatant, inhibited the intracellular calcium increase induced by ligation of the T cell antigen receptor, leading to inhibition of NFAT-dependent cytokine production. We have also found two other effects of CE cells on T cells; lymphocyte viability in cultures is enhanced by a CE cell factor, and expression of some T cell surface markers, such as CD8alpha, Thy 1, and CD45RC are altered following incubation with CE cells or conditioned medium. The identification and characterization of the factor(s) that mediates these novel effects are the goals of this study. We propose to: 1. use expression cloning of a CE cell library to find the activity(s); 2. identify the activity(s) to learn if it is a known factor(s); and 3. if the activity has not already been described, continue characterization of the factor(s) and mechanism of action.
Funding Period: 2001-02-01 - 2004-07-31
more information: NIH RePORT