A better understanding of Type 1 diabetes (T1D) pathogenesis has enabled development of immunomodulatory strategies aimed at inducing clinical remission. While much has been learned, the positive effects observed in these trials have generally been of limited duration and patient responses have been mixed. New measures of immune activity are needed to define mechanisms that could enable selection of targeted, personalized therapies; monitor changes in the immune state associated with responses to treatment, and serve as surrogate outcomes to shorten the duration of clinical trials. To fill thi gap we have employed an array-based bioassay, where subject serum/plasma is used to induce transcriptional responses in a well-controlled peripheral blood mononuclear cell population. We find that pre and new onset T1D plasma induces a disease-specific, partially interleukin (IL)-1 dependent signature relative to related and unrelated healthy controls. We have used this approach to study participants of the Interleukin-1 in Diabetes Action and TrialNet Canakinumab trials. Overall, these trials did not show efficacy of IL-1 receptor antagonist (IL-1RA) or canakinumab therapy in preserving ?-cell function in T1D patients. However, our analyses revealed that varying levels of the anticipated immunomodulation was achieved with either therapeutic and an inverse relationship was observed between the inflammatory signature and stimulated C-peptide area under the curve. We hypothesize that application of this approach to clinical trials representing a spectrum of immunomodulatory strategies beyond IL-1 antagonism will allow 1) a molecular definition of the therapeutic response within each study; and 2) a determination whether mechanistically similar alterations in the inflammatory state contributed to positive responses across the trials. We propose the following Specific Aims:
Aim 1 : To define the molecular signature associated with target antigen immunization through temporal analysis of RO T1D patients participating in the GAD-alum immunization trial.
Aim 2 : To define the molecular signatures associated with impairment of immunocyte replication/interaction through temporal analysis of RO T1D patients participating in the Mycophenolate Mofetil-Daclizumab (MMF/DZB) and CTLA-4-Ig (Abatacept) trials.
Aim 3 : To define the molecular signature associated with B-lymphocyte ablation through temporal analysis of RO T1D patients participating in the anti-CD20 (Rituximab) trial.
This project will benefit future Type 1 Diabetes (T1D) trials by defining the common and unique effects past trials had on the inflammatory state and provide insight as to the combination of immunological pathways that must be targeted to recapitulate the immune state observed in healthy subjects.
| Cabrera, Susanne M; Engle, Samuel; Kaldunski, Mary et al. (2018) Innate immune activity as a predictor of persistent insulin secretion and association with responsiveness to CTLA4-Ig treatment in recent-onset type 1 diabetes. Diabetologia 61:2356-2370 |
| Tsai, Susan; McOlash, Laura; Jia, Shuang et al. (2018) A serum-induced transcriptome and serum cytokine signature obtained at diagnosis correlates with the development of early pancreatic ductal adenocarcinoma metastasis. Cancer Epidemiol Biomarkers Prev : |
