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disease including collagen-induced arthritis (CIA), experimental allergic encephalomyelitis (EAE) and, in more recent unpublished observations, block the progression from recent onset hyperglycemia to overt type 1 diabetes (T1D) in non-obese diabetic (NOD) mice.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.
| Söderström, Kalle; Stein, Emily; Colmenero, Paula et al. (2010) Natural killer cells trigger osteoclastogenesis and bone destruction in arthritis. Proc Natl Acad Sci U S A 107:13028-33 |
| Creusot, Remi J; Yaghoubi, Shahriar S; Kodama, Keiichi et al. (2008) Tissue-targeted therapy of autoimmune diabetes using dendritic cells transduced to express IL-4 in NOD mice. Clin Immunol 127:176-87 |
| Yaghoubi, Shahriar S; Creusot, Remi J; Ray, Pritha et al. (2007) Multimodality imaging of T-cell hybridoma trafficking in collagen-induced arthritic mice: image-based estimation of the number of cells accumulating in mouse paws. J Biomed Opt 12:064025 |
