Prolactin as an Adjunct for Type 1 Diabetes Immunotherapy

Abstract

Type 1 diabetes is caused by autoimmune destruction of β-cells. Although immunotherapy can restore self-tolerance thereby halting continued immune-mediated β-cell loss, residual β-cell mass and function is often insufficient for normoglycemia. Using a growth factor to boost β-cell mass can potentially overcome this barrier and prolactin (PRL) may fill this role. Previous studies have shown that PRL can stimulate β-cell proliferation and up-regulate insulin synthesis and secretion while reducing lymphocytic infiltration of islets, suggesting that it may restore normoglycemia through complementary mechanisms. Here, we test the hypothesis that PRL can improve the efficacy of an immune modulator, the anticluster of differentiation 3 monoclonal antibody (aCD3), in inducing diabetes remission by up-regulating β-cell mass and function. Diabetic nonobese diabetic (NOD) mice were treated with a 5-day course of aCD3 with or without a concurrent 3-week course of PRL. We found that a higher proportion of diabetic mice treated with the aCD3 and PRL combined therapy achieved diabetes reversal than those treated with aCD3 alone. The aCD3 and PRL combined group had a higher β-cell proliferation rate, an increased β-cell fraction, larger islets, higher pancreatic insulin content, and greater glucose-stimulated insulin release. Lineage-tracing analysis found minimal contribution of β-cell neogenesis to the formation of new β-cells. Although we did not detect a significant difference in the number or proliferative capacity of T cells, we observed a higher proportion of insulitis-free islets in the aCD3 and PRL group. These results suggest that combining a growth factor with an immunotherapy may be an effective treatment paradigm for autoimmune diabetes.

Oligofructose as an adjunct in treatment of diabetes in NOD mice

“…1B), although the average blood glucose of the aCD3-alone group tended to be higher than the aCD3 + OFS group throughout the IPGTT. The non-diabetic normal control mice and the aCD3-alone group had similar responses during the IPGTT and ITT, as we previously observed27. Of note, the aCD3-alone and the aCD3 + OFS groups had similar body weights at the time of sacrifice (aCD3: 23.08 ± 0.43 g vs. aCD3 + OFS: 23.35 ± 0.23 g).…”

“…We chose OFS because studies have shown that it improves insulin sensitivity in obesity1115282930, which may result in lower insulin requirement and improved glucose homeostasis. Our immunotherapy of choice was the anti-CD3 monoclonal antibody (aCD3) because it is a well-characterized agent that induces permanent diabetes remission in up to 60% of NOD mice452731, and it has been used in several human trials, demonstrating some efficacy in slowing the process of beta-cell destruction67832. In this study, we found that when given in conjunction with aCD3, OFS improves the aCD3-mediated diabetes reversal rate in NOD mice, accompanied by an improvement in insulin sensitivity, a reduction in insulitis, and an increase in beta-cell proliferation rate and insulin secretion.…”

“…For those receiving both aCD3 and OFS, starting on day 1 of diabetes, 10% OFS (Orafti P95, mixed with normal chow at 1:9 ratio) was provided daily in a food cup for ensuing 8 weeks. We chose an 8-week OFS treatment period because previous work in obese rats showed that 6–8 weeks of OFS was sufficient to induce metabolic benefits and a change in gut microbiota1527. Blood glucose was monitored twice weekly and diabetes reversal/free was defined as random serum glucose <11 mmol/L for at least 3 consecutive weeks.…”

Replicative capacity of β-cells and type 1 diabetes

“…Some peptide hormones, including parathyroid hormone-related protein (PTHrP) [31,32] and prolactin [33,34], stimulate β-cell replication in vitro and are known mitogens of compensatory β-cell proliferation during rodent pregnancy. Recently it was shown that PRLR-Jak2-Stat5 signaling is not prominent in human β-cells; interestingly, however, murine Stat5a induced proliferation of human β-cells [15] and there is evidence that prolactin may augment traditional T1D therapies [35]. Signaling of steroid hormones progesterone, estrogen, and androgen modulates proliferation, and is disrupted under diabetic conditions [14,34].…”

Interactions Between the Neuroendocrine System and T Lymphocytes in Diabetes

“…Further studies in this latter experimental model showed that PRL treatment enhances a Th2 response by increasing the frequency of IL-10 positive splenocytes and down-modulating the featured expression of the Th1 cytokines IFN-γ and TNF-α in splenocytes ( 231 ). Furthermore, PRL-expanded Treg (CD4 + Foxp3 + ) population and improved the efficacy of short-term low-dose anti-CD3 treatment (which induce a transient CD4 + and CD8 + T cell depletion) at achieving diabetes remission in the NOD mice ( 232 ). Conversely, severe hyperprolactinemia induced by anterior pituitary ectopic transplantation increases the incidence of diabetes in the NOD mice ( 233 ).…”