We postulate that activated mucosal T-cells are pivotal to the development of intestinal mucosal inflammation characteristic of ulcerative colitis (UC). The overall objective of this project is to define specific lymphoid populations and their cytokine and cytotoxic products contributing to the mucosal inflammation of human UC in comparison with the ulcerative colitis-like IL-2(-/-) transgenic mouse. In addition, we will test the therapeutic efficacy of recombinant cytokines and novel cytokine fusion molecules in the IL-2(-/-) model of colonic inflammation.
Specific Aim 1. To test the hypothesis that the balance of expression of immunosuppressive and pro-inflammatory molecules within the intestinal mucosa of patients with active UC is tilted toward expression of certain pro-inflammatory cytokines.
Specific Aim 2. To test the hypothesis that T-cell subpopulations are responsible for causing colitis in the established IL-2(-/-) transgenic UC-like mouse model.
Specific Aim 3. To test the therapeutic potential of IL-2, IL-10 and novel recombinant fusion proteins that employ cytokines (IL-2 or IL-4) as the cellular targeting domain and truncated diphtheria toxin or immunoglobulin related peptides as the cytotoxic element (e.g. IL-2 diphtheria toxin) in the IL-2(-/-) transgenic UC animal model.
Specific Aim 4. To develop a humanized animal model of chronic mucosal inflammation by introducing human UC lymphocyte populations into newly developed and stable immunodeficient transgenic animals CD3epsilonH(+/+) (T cell and NK cell deficient mice) and RAG 2(-/-) (T and B cell deficient mice).
| Stevens, A C; Matthews, J; Andres, P et al. (1997) Interleukin-15 signals T84 colonic epithelial cells in the absence of the interleukin-2 receptor beta-chain. Am J Physiol 272:G1201-8 |
| Bousvaros, A; Stevens, A C; Strom, T B et al. (1997) Interleukin-2 fusion protein (DAB389IL-2) selectively targets activated human peripheral blood and lamina propria lymphocytes. Dig Dis Sci 42:1542-8 |
