Project description:Anti-CD3 mAb delays or prevents type 1 diabetes (T1D) by modulating the immune mediated destruction of beta cells. Our findings described the reshaping of islet-infiltrating T cells and beta cells that lead to operational, but tenuous tolerance to autoimmune diabetes following anti-CD3 mAb treatment.
Project description:Type 1 diabetes (T1D) results from autoimmune destruction of β cells in the pancreas. Protein tyrosine phosphatases (PTPs) are candidate genes for T1D and play a key role in autoimmune disease development and β-cell function. Here, we assessed the global protein and individual PTP profile in the pancreas of diabetic NOD mice treated with anti-CD3 mAb and IL-1RA combination therapy. The treatment reversed hyperglycemia compared to the anti-CD3 alone control group. We observed enhanced expression of PTPN2, a T1D candidate gene, and endoplasmic reticulum (ER) chaperones in the islets from cured mice.
Project description:T-cell acute lymphoblastic leukemia is a hematological malignancy treated by chemotherapy, with a poor prognosis. We have demonstrated that activation of the T cell receptor (TCR) by anti-CD3 antibodies has a potent anti-leukemic effect in patient-derived xenograft models (PDX) of T-ALL. Therefore, with this experiment, we aim to identify the molecular mechanisms underlying the anti-leukemic properties of the OKT3 anti-CD3 mAb in T-ALL PDX.
Project description:CD25 monoclonal antibody binding to the alpha-chain of the Interleukin-2 (IL-2) receptor, blocks high affinity IL-2 binding thereby preventing complete T cell activation and being of ample importance in transplantation medicine and potentially the treatment of autoimmune disease. However, CD25 antibodies do not only block T cell activation but also prevent activation induced cell death (AICD) attributing a dual function to IL-2. In this study, the modulation of the genomic expression profile of human peripheral blood mononuclear cells (PBMC) with therapeutic concentrations of humanized anti-CD25 mAb was investigated. PBMC were stimulated with CD3 antibody OKT-3 together with recombinant IL-2 in the absence or presence of anti-CD25 mAb. RNA was extracted and subjected to microarray analysis on U133A microarrays (Affymetrix). The expression profile revealed the up-regulation of 62 genes and down-regulation of 38 genes by anti-CD25 mAb, respectively.
Project description:We performed a global gene expression analysis comparing intragraft tolerant CD8+ T cells from CD3 antibody-treated mice showing permanent islet graft survival to intra-graft effector CD8+ T cells isolated from untreated mice showing acute rejection of islet allografts. The objective was to emphasize the anergic profile of CD8+ T cells residing within the pancreatic islet allograft of mice rendered tolerant following CD3 antibody therapy.
Project description:T-cell acute lymphoblastic leukemia is an aggressive hematological malignancy treated with chemotherapy and has a poor prognosis. In previous studies, we demonstrated that T cell receptor (TCR)-induced negative selection is highly effective in combating T-ALL in mouse models. Moreover, targeting the TCR of diagnostic T-ALL-derived PDX with anti-hCD3 (aCD3) mAb OKT3 or the clinically relevant aCD3 mAb Teplizumab resulted in leukemic cell death, regression of leukemia, and improved host survival. The objective of the present experiment is to uncover the molecular mechanisms responsible for the anti-leukemic properties of the anti-CD3 mAbs OKT3 and Teplizumab in a T-ALL PDX model. We compare the transcriptomic profiles of FACS-sorted T-ALL cells extracted from T-ALL patient-derived xenograft (PDX) treated for 6h with isotype control antibody IgG2a or OKT3 mAb or Teplizumab mAb.