Prolactin: An Effective Partner for Anti-CD3 in Treating Type 1 Diabetes.

Abstract

Diabetes mellitus is a metabolic disease that affects about 6% of the adult population worldwide (1, 2). According to recent estimates from the World Health Organization, by 2030, the prevalence of diabetes will increase by 50% (3). There are 2 types of diabetes, type 1 diabetes (T1D) and T2D. T1D accounts for 5%–10% of all diabetes cases and is believed to result from a spontaneous or environmentally triggered T-lymphocyte-mediated autoimmune attack on the pancreatic insulin-producing -cells through recognition of islet autoantigens. On the other hand, T2D results from insulin resistance in the liver, skeletal muscle, and adipocytes, which eventually leads to -cell deficiency, -cell dysfunction, and -cell failure that may impair glucose metabolism (4). Although T2D affects significantly more people than T1D, the early onset of T1D and its serious influence upon patients’ health make it one of the most common diseases to be studied for effective therapeutic strategies. At the time of T1D diagnosis, most the -cell mass has been lost or damaged, leading the patient to require exogenous insulin supplementation or -cell replacement (eg, islet or -cell transplantation), to maintain glucose control and avoid the occurrence of potentially fatal diabetic complications (1–3). However, neither insulin supplementation nor islet transplantation is a perfect cure for T1D. Although in T1D insulin supplementation is not able to adjust the blood glucose within a delicate range, autoreactive T cells also continuously attack residue -cells and transplanted donor -cells, resulting in abolishment of the therapeutic gains, and ultimately, increased severity of disease (1, 3). In order to stop chronic immune attacks on -cells in T1D, the effects of immunotherapy have been extensively studied in the past, resulting in the discovery of anti-CD3 monoclonal antibody as a successful approach. In 1992, Herold et al (5) showed that the F(ab )2 fragments had an advantage over whole anti-CD3 monoclonal antibody in treating experimental autoimmune diabetes, in that they minimized induction of T-cell activation in vivo, which is a deleterious side effect of application of anti-CD3 monoclonal antibody clinically (5). In the same year, the merits of using anti-CD3 monoclonal antibody against experimental autoimmune diabetes were independently reported by Vallera et al (6). Later on, application of anti-CD3 monoclonal antibody was shown to cause diabetes remission in the nonobese diabetic (NOD) mouse, a model for T1D in humans (7). Moreover, treatment with anti-CD3 monoclonal antibody also slowed down the progression of T1D in patients who had remaining endogenous insulin synthesis capacity at diagnosis (8), suggesting that anti-CD3 therapy may protect remaining -cell function (9). In all these pioneer studies, the data suggest that the subjects with higher intact levels of -cell function and -cell mass may have an improved response to anti-CD3 monoclonal antibody, which implies that an adjunct therapy to protect or increase residual -cell mass and function may improve the therapeutic potential of anti-CD3 monoclonal antibody. In the past decades, generation of -cells for diabetes therapy has been one of the top priorities in the field of diabetes research. It is nowgenerallybelieved that inadulthood, new -cells are mainly generated from self-replication of existing -cells (10–14), whereas some evidence suggests that -cells can be formed from non-cells, eg, duct cells, acinar cells, nonendocrine cells, and bone