Prior ultraviolet radiation exposure of humans can result in antigen specific immunologic unresponsiveness and tolerance instead of the normal development of contact sensitivity, s has previously been demonstrated in rodent systems. The down regulation of both human and murine contact sensitivity is correlated with an influx of macrophagic class II MHC+ CD11b+ antigen presenting cells (APC's) into the epidermis after UV exposure. In mouse and man, we have demonstrated that class II MHC+ CD11b+ cells which infiltrate sunburned epidermis are responsible for the activation of antigen-naive T cells to become down regulatory for murine in vivo immunization and human in vitro lymphocyte activation.
The first aim of this proposal is to determine distinctive characteristics of DR+ UV-exposed human epidermal APC's that might form the basis of altered primary T cell activation leading to suppression, rather than antigenic reactivity. We will quantitate expression of functionally important surface molecules which function as costimulatory ligands for T cell activation or that modulate APC function. the cytokine profile of DR+ APC's in normal and UV-exposed epidermis will be assessed to determine if different immunoregulatory molecules are released into the milieu of the APC-T cell conjugate. We have in place several techniques that will allow us to perform these studies on the limited numbers of cells that we can obtain from human skin. These include triple color flow cytometric analysis of surface markers and cytokine content, and a sensitive PCR-based hybridization protocol for quantitation of APC and T cell mRNA levels.
The second aim of the proposal is to identify whether early differentiation events in the transition of antigen-naive T lymphocytes into early memory T cells can be recognized as differential T cell activation gene induction profiles in response to signalling by APC's in normal and sunburned epidermis. Identification of distinctive anergy or lymphokine gene profiles will allow us to perform experiments with blocking antibodies and antisense oligonucleotides to determine which of the differential determinants identified in Aim I are responsible for induction of the altered T cell activation gene profile. These studies are relevant to how UV light initiates down regulation of tumor, microbial, and vaccine responses, and how UV induces photosensitivity diseases and inflammatory mechanisms that may lead to photoaging and heliodermatitis in human beings. Such data on the impact of UV-injury on human health is increasingly important as stratospheric ozone thins. The results will also provide basic information regarding differential immunoregulatory control at the level of the APC, and on regulatory pathways that prevent excessive autoreactivity.
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