TRANSPLANT IMMUNOSUPPRESSION WITH ANTISENSE TECHNOLOGY

描述：(改编自申请人的摘要)虽然 同种异体肾移植一年达到80-90%，五年达到70%-80% 存活的大鼠，大多数同种异体移植物(50%-80%)在 移植后前三个月，由于急性排斥反应。 以环孢素(CsA)为基础的免疫抑制治疗窗口较窄， 从而导致毒性或过度免疫抑制。目前的研究 重点介绍了一种新型靶向无毒基因的应用 免疫抑制治疗有望诱导移植耐受。 设计用于抑制细胞基因表达的寡核苷酸 通过Watson-Crick配对杂交特定的信使RNA。反义词 硫代寡核苷酸(PS-OGO)被设计用于靶向 参与细胞间黏附的分子以及所需的分子 用于激活T和B细胞。先前的研究表明，使用 细胞间黏附分子-1、血管黏附分子-1 血管细胞黏附分子-1或c-raf反义PS-寡核苷酸延长心脏存活时间 以剂量依赖和序列特定的方式进行同种异体移植。现在时 实验将检测内皮细胞-白细胞黏附分子 (E-选择素)、白细胞功能相关抗原分子-1(LFA-1) 移植肾、心脏和小肠的存活情况。T细胞识别 通过由α和β组成的T细胞受体(TCR)的同种异体抗原 链；每个链由可变区(V)和恒定区组成。因此，Vbeta8 反义PS寡核苷酸可阻断大鼠同种异体器官移植排斥反应 同种异体抗原特有的方式。B7反义PS-寡核苷酸(二次激活 信号)或/和白介素2/干扰素(干扰素)-u反义 PS-寡核苷酸(封闭T辅助分子1)可诱导移植耐受。这个 将检测C-RAF、蛋白C(PKC)、RAS和Lck PS-寡聚糖以阻断T 细胞功能与心脏移植排斥反应。B细胞识别同种异体抗原 通过免疫球蛋白(Ig)的B细胞受体(BCR)，即IgM(Mu)、IgG1 、IgG2a(Gamma2a)、IgG2b(Gamma2b)或IgG3(Gamma3)bcr；反义 靶向这些不同表位(Mu，Gamma1，Gamma2a，Gamma2b， Gamma3)可以选择性地阻断针对同种异体抗原的抗体产生。在……里面 此外，在γ-1和IL-4的联合作用下，反义PS-寡核苷酸可能会抑制 免疫球蛋白类转成IgG1、Gamma2a和T细胞生长因子-β(TGF-β) 针对免疫球蛋白的反义PS-寡核苷酸，以及针对 IgG2b。PS-寡核苷酸技术提供有效且无毒的基因靶向 免疫抑制，可能会彻底改变器官的治疗方案 移植。与单抗相比，PS-寡聚糖不能 诱导产生抗寡核苷酸特异性抗体。

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.