Adoptive Cellular Gene Therapy in Type 1 Diabetes (T1D)

描述(由申请人提供)： Fathman博士的实验室发表的研究表明，通过逆转录病毒转导表达免疫调节蛋白的小鼠T细胞杂交瘤，可以阻止包括胶原诱导性关节炎(CIA)、实验性变态反应性脑脊髓炎(EAE)在内的几种自身免疫性疾病小鼠模型的疾病诱导或疾病进展，并在最近未发表的观察中，阻止非肥胖糖尿病(NOD)小鼠从新近发病的高血糖向显性1型糖尿病(T1D)的进展。最近这些意想不到的发现为在新近发病的高血糖阶段对人类T1D进行干预提供了潜在的可能性，一种形式的“过继细胞基因疗法”可能被扩展到预防从胰岛素炎到高血糖的进展，不仅在NOD小鼠中，而且在“高风险”糖尿病前期人类T1D中。从胰岛抗原反应性小鼠T细胞杂交瘤转变为用于T1D基因治疗的小鼠自体树突状细胞所需的技术，作为R21开发和治疗T1D新近发病的高血糖的可行性方法的一部分。最近获得的初步数据支持这样的假设，即树突状细胞(DC)在递送治疗调节蛋白(S)到自身免疫炎性病变方面与T细胞杂交瘤一样有效。拟议的R21研究的第二个主要目标(将继续到R33的资助)是使用cDNA微阵列技术试图了解这种形式的治疗的机制(S)，以及潜在地识别成功的替代标记或确定治疗干预的其他靶点。此外，还建议使用单纯疱疹病毒1型胸苷激酶(HSV1-tk)作为标记，实时跟踪过继转移的DC在NOD小鼠(R21)体内的转运情况，并利用这一知识将成像技术转移到MAN(R33)。最后，在请求R33支持的情况下，建议对最近高血糖的T1D患者进行转导和输注自体DC的I期试验，以进行安全性研究和观察细胞转运。

DESCRIPTION (provided by applicant): Published studies from Dr. Fathman's laboratory have demonstrated that murine T cell hybridomas, retrovirally transduced to express immunoregulatory proteins, can halt the induction or progression of disease in several mouse models of autoimmune disease including collagen-induced arthritis (CIA), experimental allergic encephalomyelitis (EAE) and, in more recent unpublished observations, block the progression from recent onset hyperglycemia to overt type 1 diabetes (T1D) in non-obese diabetic (NOD) mice. These recent unexpected findings offer the potential to intervene in human T1D at the stage of recent onset hyperglycemia with a form of "adoptive cellular gene therapy" that may potentially be extended to the prevention of progression from insulitis to hyperglycemia, not only in the NOD mouse, but in "high risk" pre-diabetic human T1D. The technology required to move from islet-antigen-reactive murine T cell hybridomas, as vehicles for "drug delivery," to murine autologous dendritic cells for gene therapy of T1D, is requested as part of this R21 development and feasibility approach to the treatment of recent onset hyperglycemia in T1D. Preliminary data, obtained recently, support the hypothesis that dendritic cells (DCs) are as effective as T cell hybridomas in delivering the therapeutic regulatory protein(s) to the inflammatory lesions of autoimmunity. A second major goal of the proposed R21 studies (that will continue into the R33 funding) is to use cDNA microarray technology to attempt to understand the mechanism(s) of this form of therapy, as well as potentially identify surrogate markers of success or identify additional targets for therapeutic intervention. It is additionally proposed to use herpes simplex virus type 1 thymidine kinase (HSV1-tk) as a marker to follow the trafficking of adoptively transferred DCs in real time in vivo in NOD mice (R21) and to use this knowledge to transfer the imaging technology to man (R33). Finally, under requested R33 support, a Phase I trial of transduction and infusion of autologous DCs into recently hyperglycemic T1D patients for safety studies and to observe cell trafficking is proposed.