Thomas Donner

Interleukin-10 paradox: A potent immunoregulatory cytokine that has been difficult to harness for immunotherapy.

Interleukin-10 (IL-10) is arguably the most potent anti-inflammatory cytokine. It is produced by almost all the innate and adaptive immune cells. These cells also serve as its targets, indicating that IL-10 secretion and action is highly regulated and perhaps compartmentalized. Consistent with this notion, various efforts directed at systemic administration of IL-10 to modulate autoimmune diseases (type 1 diabetes, multiple sclerosis, rheumatoid arthritis, psoriasis) have produced conflicting and largely inconsequential effects. On the other hand, IL-10 can promote humoral immune responses, enhancing class II expression on B cells and inducing immunoglobulin (Ig) production. Consequently, the high IL-10 level in systemic lupus erythematosus (SLE) patients is considered pathogenic and its blockade ameliorates the disease. In this perspective, we review preclinical findings and results of recent clinical studies using exogenous IL-10 to treat the aforementioned autoimmune diseases. In addition, given the limited success of IL-10 supplementation, we suggest that future studies should be expanded beyond modulating the delivery modes to include developing new strategies to protect and replenish the endogenous sources of IL-10. As an example, we provide evidence that aberrant Fas-mediated deletion of IL-10-producing B cells subverts the immunoregulatory role of IL-10 in autoimmune diabetes and that modulation of the Fas pathway preserves the IL-10-producing B cells and completely protects NOD mice from developing the disease.

Low-Dose Otelixizumab Anti-CD3 Monoclonal Antibody DEFEND-1 Study: Results of the Randomized Phase III Study in Recent-Onset Human Type 1 Diabetes

OBJECTIVE Previous studies demonstrated that the anti-CD3 monoclonal antibody otelixizumab, administered at a total dose of 48–64 mg, can slow the loss of C-peptide in recent-onset type 1 diabetes patients, with frequent reactivation of Epstein Barr virus (EBV). The DEFEND-1 (Durable Response Therapy Evaluation for Early or New-Onset Type 1 Diabetes) trial was designed to test whether a lower dose of otelixizumab could preserve C-peptide secretion in new-onset type 1 diabetes patients. RESEARCH DESIGN AND METHODS A multicenter, randomized, placebo-controlled trial was performed in sites in the U.S., Canada, and Europe. Two hundred eighty-one patients were randomized to treatment with 3.1 mg otelixizumab administered over 8 days or placebo. The primary end point of the study was the change in C-peptide area under the curve (AUC) from a 2-h mixed-meal tolerance test at month 12. RESULTS The change in 2-h C-peptide AUC was not different between placebo-treated patients and otelixizumab-treated patients (−0.20 vs. −0.22 nmol/L, P = 0.81). Secondary end points, including HbA1c, glucose variability, and insulin dose, were also not statistically different between the two groups. More patients in the otelixizumab group than in the placebo group experienced adverse events, mostly grade 1 or grade 2. There was no EBV reactivation (viral load >10,000 copies/106 peripheral blood mononuclear cells) in the otelixizumab group, in contrast with previously published studies at higher doses of otelixizumab. CONCLUSIONS Otelixizumab was well tolerated in patients with recent-onset type 1 diabetes at a total dose of 3.1 mg, but did not achieve preservation of levels of C-peptide or other markers of metabolic control.

Rosiglitazone and Outcomes for Patients With Diabetes Mellitus and Coronary Artery Disease in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) Trial

Background— Rosiglitazone improves glycemic control for patients with type 2 diabetes mellitus, but there remains controversy regarding an observed association with cardiovascular hazard. The cardiovascular effects of rosiglitazone for patients with coronary artery disease remain unknown. Methods and Results— To examine any association between rosiglitazone use and cardiovascular events among patients with diabetes mellitus and coronary artery disease, we analyzed events among 2368 patients with type 2 diabetes mellitus and coronary artery disease in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial. Total mortality, composite death, myocardial infarction, and stroke, and the individual incidence of death, myocardial infarction, stroke, congestive heart failure, and fractures, were compared during 4.5 years of follow-up among patients treated with rosiglitazone versus patients not receiving a thiazolidinedione by use of Cox proportional hazards and Kaplan–Meier analyses that included propensity matching. After multivariable adjustment, among patients treated with rosiglitazone, mortality was similar (hazard ratio [HR], 0.83; 95% confidence interval [CI], 0.58–1.18), whereas there was a lower incidence of composite death, myocardial infarction, and stroke (HR, 0.72; 95% CI, 0.55–0.93) and stroke (HR, 0.36; 95% CI, 0.16–0.86) and a higher incidence of fractures (HR, 1.62; 95% CI, 1.05–2.51); the incidence of myocardial infarction (HR, 0.77; 95% CI, 0.54–1.10) and congestive heart failure (HR, 1.22; 95% CI, 0.84–1.82) did not differ significantly. Among propensity-matched patients, rates of major ischemic cardiovascular events and congestive heart failure were not significantly different. Conclusions— Among patients with type 2 diabetes mellitus and coronary artery disease in the BARI 2D trial, neither on-treatment nor propensity-matched analysis supported an association of rosiglitazone treatment with an increase in major ischemic cardiovascular events. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00006305.

Update on insulin therapy for type 2 diabetes.

Type 2 diabetes is characterized by insulin resistance and impaired insulin secretion at diagnosis and by progressive β-cell dysfunction over time. Insulin therapy is thus frequently required during the course of the disease to maintain glycemic control and prevent diabetes complications. Insulin should be initiated when alternative antihyperglycemic agents have failed or when symptomatic or marked hyperglycemia is present. Recent studies demonstrate that the addition of basal, prandial, basal/bolus, or premixed insulins to existing antihyperglycemic regimens effectively lowers glycosylated hemoglobin (HbA1c). The long-acting insulin analogs cause less nocturnal hypoglycemia than bedtime NPH, with comparable HbA1c reductions. Insulin detemir confers a weight advantage over glargine or NPH. Rapid-acting insulin analogs control postprandial hyperglycemia more effectively than regular insulin and modestly lower HbA1c. For selected patients with severe insulin resistance, U-500 is a less expensive and potentially more effective alternative to U-100 insulin. Adverse effects of insulin, including weight gain and hypoglycemia, can be minimized by initial use of basal insulins in combination with metformin, incretin mimetics, or dipeptidyl-peptidase-IV inhibitors. Although in vitro studies suggest that hyperinsulinemia may promote tumorigenesis, no currently available insulin has been shown to increase cancer rates. Targeting near-normal glucose levels in insulin-treated patients should be reserved for those of younger age with a longer life expectancy, a shorter duration of diabetes, and little or no end-organ complications. A higher HbA1c target of 7–8% is more appropriate for patients less likely to benefit from intensive control and in those at high risk for severe hypoglycemia.

US Trends in Glycemic Control, Treatment, and Comorbidity Burden in Patients With Diabetes

J Clin Hypertens (Greenwich). 2010;12:826‐832.

The potential of Fas ligand (apoptosis-inducing molecule) as an unconventional therapeutic target in type 1 diabetes

The development of type 1 diabetes (T1D) is driven by autoreactive T cells that attack and destroy the insulin-producing β-cells in pancreatic islets, forcing patients to take multiple daily insulin injections. Insulin therapy, however, is not a cure and diabetic patients often develop serious long-term microvascular and cardiovascular complications. Therefore, intensive efforts are being directed toward developing safe immunotherapy for the disease that does not impair host defense and preserves β-cells, leading to better glycemic control than exogenous insulin therapy. Engineering therapies that differentially cripple or tolerate autoreactive diabetogenic T cells while sparing protective T cells necessary for maintaining a competent immune system has proven challenging. Instead, recent efforts have focused on modulating or resetting the immune system through global but transient deletion of T cells or B cells using anti-CD3 or anti-CD20 mAb, respectively. However, phase III clinical trials have shown promising but modest efficacy so far with these approaches. Therefore, there is a need to identify novel biological targets that do not fit the classic properties of being involved in adaptive immune cell activation. In this prospective, we provide preclinical evidence that targeting Fas ligand (FasL) may provide a unique opportunity to prevent or cure T1D and perhaps other organ-specific autoimmune diseases without causing immune suppression. Unlike conventional targets that are involved in T and B lymphocyte activation (such as CD3 and CD20, respectively), FasL is an apoptosis-inducing surface molecule that triggers cell death by binding to Fas (also known as CD95 Apo-1). Therefore, targeting FasL is not expected to cause immune suppression, the Achilles Heel of conventional approaches. We will discuss the hypothesis that targeting FasL has unique benefits that are not offered by current immunomodulatory approaches.

Cardiovascular Effects of Noninsulin, Glucose-Lowering Agents: Need for More Outcomes Data

Macrovascular complications of type 2 diabetes mellitus (DM) are primarily driven by the combination of underlying atherosclerosis and propensity for thrombosis. Prevention of macrovascular complications in DM relies on therapies directed at multiple coexisting intermediary pathophysiologies that contribute to cardiovascular events, including hyperglycemia, lipoprotein abnormalities, hypertension, inflammation, and propensity for thrombosis. Multiple noninsulin, glucose-lowering agents have been developed that effectively lower blood glucose levels. This review explores the literature on the cardiovascular benefits and harms associated with these therapies, with an emphasis on cardiovascular outcomes when available. The lack of long-term data on cardiovascular outcomes regarding safety and efficacy of available traditional glucose-lowering agents has led to recommendations for more thorough evaluations of new therapies before approval. Furthermore, recent data suggest harm from intensive hemoglobin A(1c) reductions. Accordingly, there are multiple, large, cardiovascular-event driven phase 3-4 trials of therapies from the incretin axis currently enrolling. Recommendations for a therapeutic approach with noninsulin, glucose-lowering agents for the prevention of cardiovascular events in patients with type 2 DM are provided based on current data. Ultimately, multifactorial risk interventions, including lifestyle modifications, antihyperglycemic agents, antihypertensives, statins, and aspirin remain the primary focus to prevent macrovascular complications in patients with type 2 DM.

Expansion of FasL-Expressing CD5+ B Cells in Type 1 Diabetes Patients

Fas ligand drives insulitis in the non-obese diabetic mouse model of type 1 diabetes (T1D) and negatively regulates IL-10-producing (IL-10pos) CD5+ B cells in pancreata. Relevance of these phenomena to the human disease is poorly understood. Here, using splenocytes from T1D, autoantibody (Ab+), and non-diabetic (ND) human subjects, we show that a subpopulation of CD5+ B cells that is characterized by expression of FasL (FasLhiCD5+) was significantly elevated in T1D subjects, many of whom had significantly reduced frequency of IL-10posCD5+ B cells compared to Ab+ subjects. The majority of FasLhiCD5+ B cells did not produce cytokines and were more highly resistant to activation-induced cell death than their IL-10posCD5+ counterparts. These results associate expansion of FasL-expressing CD5+ B cells with T1D and lay the groundwork for future mechanistic studies to understand specific role in disease pathogenesis.

Response to Letter Regarding Article, “Rosiglitazone and Outcomes for Patients With Diabetes Mellitus and Coronary Artery Disease in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) Trial”

They point out that, in contrast to our results, previous pooled analyses of randomized trials of rosiglitazone showed a higher incidence of myocardial infarction, and that our observed differences (or rather lack of differences) in cardiovascular outcomes associated with rosiglitazone were potentially attributable to residual confounding. They also raise the point that we did not report a falsification end point that could have assessed the likelihood that observed results were more likely attributable to confounding than true effects. Our study reported prospectively collected longitudinal results from the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial cohort based on the diabetes mellitus treatment received, and was not a cross-sectional analysis. We agree that there is no substitute for randomization and no observational study, ours included, can fully exclude residual confounding. We should then also note the potential weaknesses of the meta-analysis that first implicated rosiglitazone as a cause of myocardial infarction, and reemphasize the unique aspects of the BARI 2D design and analysis that would be expected to minimize the impact of confounding. Even a well-conducted meta-analysis of limited studies will remain limited, because it is unable to compensate for the weaknesses of the original studies and may even unintentionally conceal those weaknesses. A carefully performed, independent examination of the meta-analysis regarding cardiovascular hazard from rosiglitazone concluded that the risk for myocardial infarction and death for diabetic patients taking rosiglitazone remained uncertain. 2 It is within this context that the BARI 2D design and results merit further consideration. In the BARI 2D trial, 3 patients were randomly assigned to a glycemic strategy of insulin sensitization or insulin provision. Therefore, initiation of rosiglitazone was generally determined by treatment assignment rather than patient indication, and the biases seen when the initiation of drug treatment is influenced by severity of illness were minimized. We used propensity-matching to further reduce any baseline differences when comparing treatment groups. Despite this, we did not detect a signal of ischemic cardiovascular harm from rosiglitazone. Similar conclusions were recently confirmed by a thorough FDA review of the independent readjudication of the 1 completed randomized trial designed to test the cardiovascular safety of rosiglitazone. 4

IL-17 and limits of success

Interleukin-17 (IL-17) is a potent proinflammatory cytokine that protects a host against fungal and extracellular bacterial infections. On the other hand, excessive or dysregulated production of IL-17 underlines susceptibility to autoimmune disease. Consequently, blocking IL-17 has become an effective strategy for modulating several autoimmune diseases, including multiple sclerosis (MS), psoriasis, and rheumatoid arthritis (RA). Notably, however, IL-17 blockade remains ineffective or even pathogenic against important autoimmune diseases such as inflammatory bowel disease (IBD). Furthermore, the efficacy of IL-17 blockade against other autoimmune diseases, including type 1 diabetes (T1D) is currently unknown and waiting results of ongoing clinical trials. Coming years will determine whether the efficacy of IL-17 blockade is limited to certain autoimmune diseases or can be expanded to other autoimmune diseases. These efforts include new clinical trials aimed at testing second-generation agents with the goal of increasing the efficiency, spectrum, and ameliorating side effects of IL-17 blockade. Here we briefly review the roles of IL-17 in the pathogenesis of selected autoimmune diseases and provide updates on ongoing and recently completed trials of IL-17 based immunotherapies.