A Novel Clinically Relevant Strategy to Abrogate Autoimmunity and Regulate Alloimmunity in NOD Mice

Abstract

OBJECTIVETo investigate a new clinically relevant immunoregulatory strategy based on treatment with murine Thymoglobulin mATG Genzyme and CTLA4-Ig in NOD mice to prevent allo- and autoimmune activation using a stringent model of islet transplantation and diabetes reversal.RESEARCH DESIGN AND METHODSUsing allogeneic islet transplantation models as well as NOD mice with recent onset type 1 diabetes, we addressed the therapeutic efficacy and immunomodulatory mechanisms associated with a new immunoregulatory protocol based on prolonged low-dose mATG plus CTLA4-Ig.RESULTSBALB/c islets transplanted into hyperglycemic NOD mice under prolonged mATG+CTLA4-Ig treatment showed a pronounced delay in allograft rejection compared with untreated mice (mean survival time: 54 vs. 8 days, P < 0.0001). Immunologic analysis of mice receiving transplants revealed a complete abrogation of autoimmune responses and severe downregulation of alloimmunity in response to treatment. The striking effect on autoimmunity was confirmed by 100% diabetes reversal in newly hyperglycemic NOD mice and 100% indefinite survival of syngeneic islet transplantation (NOD.SCID into NOD mice).CONCLUSIONSThe capacity to regulate alloimmunity and to abrogate the autoimmune response in NOD mice in different settings confirmed that prolonged mATG+CTLA4-Ig treatment is a clinically relevant strategy to translate to humans with type 1 diabetes.

Contribution of Different Mechanisms to Pancreatic Beta-cell Hyper-secretion in Non-obese Diabetic (NOD) Mice during Pre-diabetes

“…NOD mice that developed overt diabetes (basal non-fasting glycemia Ͼ11 mM) were excluded from the experiment. Balb/c mice are nondiabetic, and their islets are often used as donor for allogenic islet transplantation to NOD mice (8). Therefore, age-matched Balb/c female mice were purchased from Vital River Experimental Animal Company (Beijing, China) to be used as the control.…”

Prognostic implications of immunosuppressive protein expression in tumors as well as immune cell infiltration within the tumor microenvironment in gastric cancer

“…), and PD-1(?) cells in the tumor microenvironment were assessed using a previously described image analysis system [13,14] These median values were cut-off points for high-CD3 (vs. low-CD3), high-CD4 (vs. low-CD4), high-CD8 (vs. low-CD8), and high-PD-1 (vs. low-PD-1) cases (Fig. S1 of the ESM).…”

Systemic inflammation is associated with the density of immune cells in the tumor microenvironment of gastric cancer

“…, and CD8 ? immune cells in the tumor microenvironment were assessed with a previously described image analysis system [27,28]. Arrays were stained with the following primary antibodies: rabbit polyclonal anti-CD3 (1:100 dilution, Dako, Glostrup, Denmark); rabbit monoclonal anti-CD4, clone SP35 (undiluted, Ventana Medical Systems, Tucson, AZ, USA); and mouse monoclonal anti-CD8, clone C8/144B (undiluted, Dako, Carpinteria, CA, USA).…”