TRANSPLANT IMMUNOSUPPRESSION WITH ANTISENSE TECHNOLOGY

点击翻译按钮获取中文摘要

DESCRIPTION: (Adapted from the applicant's abstract) Although survival of kidney allografts reached a remarkable 80-90% one year and 70-80% five year survival rats, the majority of allografts (50-80%) are affected, during first three months postgrafting, by an acute rejection episode. Cyclosporine (CsA)-based immunosuppression has narrow therapeutic window, thereby resulting in toxicity or over immunosuppression. Present study focuses on application of a new gene-targeted and non-toxic immunosuppressive treatments poised to induce transplantation tolerance. Cellular gene expression is inhibited by oligonucleotide designed to hybridize a specific messenger RNA by Watson-Crick pairing. The antisense phosphorothioated oligonuleotides (PS-oligo) are designed to target molecules involved in cell-to-cell adhesion as well as molecules required for activation of T and B cells. Previous study showed that treatment with intercellular adhesion molecule-1 (lCAM-1), vascular adhesion molecule-1 (VCAM-1), or c-raf antisense PS-oligo prolonged the survival of heart allografts in a dose-dependent and sequence specific fashion. Present experiments will examine endothelial-leukocyte adhesion molecule (E-selectin), leukocyte function-associated antigen molecule-1 (LFA-1) on the survival of kidney, heart and small bowel allografts. T cells recognize alloantigens through T cell receptor (TCR) composed of alpha and beta chains; each chain consists variable (V) and constant regions. Thus, Vbeta8 antisense PS-oligo may block the rejection of organ allografts in alloantigen-specific fashion. B7 antisense PS-oligos (second activation signal) or/and with interleukin (IL)-2/interferon (IFN)-mu antisense PS-oligos (blocking T helper 1) may induce transplantation tolerance. The c-raf, protein C (PKC), Ras, and Lck PS-oligos will be tested to block T cell functions and heart allograft rejection. B cells recognize alloantigen through immunoglobulin (Ig) B cell receptor (BCR), namely the IgM(mu), IgG1 gamma1), IgG2a(gamma2a), IgG2b (gamma2b), or IgG3 (gamma3) BCR; antisense PS-oligo targeting these different epitopes (mu, gamma1, gamma2a, gamma2b, gamma3) may selectively block antibody production to alloantigens. In addition, in combination of gamma1 and IL-4 antisense PS-oligos may inhibit Ig class switching to IgG1; gamma2a and T cell growth factor-beta (TGF-beta) antisense PS-oligos to IgGa; and gamma2b and IFN-y antisense PS-oligos to IgG2b. PS-oligo technology offer potent and nontoxic gene-targeted immunosuppression, which may revolutionize therapeutic protocols for organ transplantation. In contrast to monoclonal antibodies PS-oligos do not induce production of anti-oligo specific antibodies.