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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI039026-03
Application #
2672641
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Project Start
1996-07-01
Project End
1999-06-30
Budget Start
1998-07-01
Budget End
1999-06-30
Support Year
3
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Texas Health Science Center Houston
Department
Surgery
Type
Schools of Medicine
DUNS #
City
Houston
State
TX
Country
United States
Zip Code
77225
Stepkowski, Stanislaw M; Kao, Judy; Wang, Mou-Er et al. (2005) The Mannich base NC1153 promotes long-term allograft survival and spares the recipient from multiple toxicities. J Immunol 175:4236-46
Tian, L; Qu, X; Wang, M E et al. (2001) Selective inhibition of IL-2 mRNA blocks allograft rejection by limiting T cell clonal expansion. Transplant Proc 33:330
Qu, X; Kirken, R A; Tian, L et al. (2001) Selective inhibition of IL-2 gene expression by IL-2 antisense oligonucleotides blocks heart allograft rejection. Transplantation 72:915-23
Behbod, F; Erwin-Cohen, R A; Wang, M E et al. (2001) Concomitant inhibition of Janus kinase 3 and calcineurin-dependent signaling pathways synergistically prolongs the survival of rat heart allografts. J Immunol 166:3724-32
Stepkowski, S M; Chen, W; Bennett, C F et al. (2001) Phosphorothioate/methoxyethyl-modified ICAM-1 antisense oligonucleotides improves prevention of ischemic/reperfusion injury. Transplant Proc 33:3705-6
Chen, W; Bennett, C F; Condon, T P et al. (2001) Methoxyethyl modification of phosphorothioate ICAM-1 antisense oligonucleotides improves prevention of ischemic/reperfusion injury. Transplant Proc 33:854
Stepkowski, S M; Chen, W; Geary, R et al. (2001) Development of an oral formulation for ICAM-1 antisense oligonucleotides. Transplant Proc 33:387
Katz, S M; Bennett, F; Stecker, K et al. (2000) ICAM-1 antisense oligodeoxynucleotide improves islet allograft survival and function. Cell Transplant 9:817-28
Stepkowski, S M; Qu, X; Wang, M E et al. (2000) Inhibition of C-raf expression by antisense oligonucleotides extends heart allograft survival in rats. Transplantation 70:656-61
Stepkowski, S M (2000) Development of antisense oligodeoxynucleotides for transplantation. Curr Opin Mol Ther 2:304-17

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