Progress in immune-based therapies for type 1 diabetes

Abstract

SummaryImmune-based therapies that prevent type 1 diabetes or preserve metabolic function remaining at diagnosis have become a major objective for funding agencies and international trial consortia, and receive backing from notable patient advocate groups. The development of immune-based therapeutic strategies in this arena requires a careful balancing of the risks of the therapy against the potential benefits, because many individuals are diagnosed or identified as being at increased risk of disease in early childhood, a period when manipulation of the developing immune system should be undertaken with caution. In addition, a therapy exists (daily insulin injection) that is lifesaving in the acute stages of disease and can be used effectively over a lifetime as maintenance. Conversely, the disease is increasing in incidence; is peaking in ever-younger age groups; carries significant risk of increased morbidity and early mortality; and remains difficult to manage effectively in many settings. With these issues in mind, in this article we review progress towards immune-based strategies for this chronic autoimmune disease. Keywords: autoimmunity, diabetes, immunotherapy The perspectiveWith the exception of one or two early attempts at disease modulation, the field of immunotherapy for type 1 diabetes did not develop significant momentum until the 1980s, during which a series of studies were initiated that made use of a drug (cyclosporin) which had, by then, revolutionized immune suppression in the setting of organ transplantation. Some 20 years on from those early successes, in 2007 we reviewed the status of intervention and prevention trials for type 1 diabetes [1]. The timing of our commentary was significant; the first major advance since cyclosporin had recently emerged, notably with the publication of two studies using monoclonal antibodies (mAbs) targeting CD3 and engineered to have limited Fc binding, both of which demonstrated clinically relevant efficacy with manageable toxicity [2,3]. At that stage we discussed the fact that these drugs (subsequently emerging as teplizumab and otelixizumab) were lead agents at the head of a therapeutic pipeline of immunomodulators. These included several drugs that were emerging from the fields of transplantation immunology and as treatments for other autoimmune and inflammatory diseases, as well as disease-specific, antigen-based therapeutics. In a subsequent, related review paper we highlighted the potential and pitfalls of harnessing these agents into combinations [4], including a proposed 'designer combo' of anti-inflammatory + immune modulator + antigen. Moreover, to facilitate the pipeline, during the same period significant infrastructure was emerging in the form of clinical trial networks, within which clinical studies could be conducted to agreed and standardized designs and protocols. The exemplar of this approach is Type 1 Diabetes TrialNet (http://www.diabetestrialnet.org). There was even significant and demonstrable interest in this disease space being disp...

The time has come to test the beta cell preserving effects of exercise in patients with new onset type 1 diabetes

“…With this in mind, a number of studies over the past 30 years have attempted to preserve beta cell function in patients with type 1 diabetes [5]. Many of these trialled agents act through 'suppressing' the inflammatory autoimmune process that targets the beta cell.…”

Preserved β-Cell Function in Type 1 Diabetes by Mesenchymal Stromal Cells

“…Despite intensive research, tested treatments have this far at best only temporarily arrested the progressive loss of b-cells in type 1 diabetes (1). Retention of endogenous insulin secretion is an attractive goal, since it causes better glycemic control (2) and decreases the risk of microvascular complications and severe hypo-or hyperglycemia episodes (3,4).…”

Targeting proinsulin-reactive CD8+ T cells: a new direction for Type 1 diabetes treatment

“…Therefore, patients need life-long insulin replacement therapy to control blood glucose levels. In the past, various efforts have been undertaken to develop and assess strategies that halt disease progression [1]. Immunotherapeutic strategies have aimed either at systemic downmodulation of the immune system or targeting specific autoimmune mechanisms involved in the disease.…”

“…The calcineurin inhibitor cyclosporine A was among the first nonspecific immune suppressants to be used in T1D. Continuous treatment initiated soon after disease onset demonstrated that it was possible to preserve b-cell function, with patients experiencing insulin independency [1]. However, this effect was short lasting and associated with accelerated renal dysfunction [2].…”

“…The enthusiasm for the use of this and other non-specific immune suppressants faded with trials using azathioprine, prednisolone and anti-thymocyte globulin showing no lasting clinical efficacy [1]. Clearly, the development of an antigenspecific therapy selectively targeting pathogenic autoreactive T cells, while sparing the ability of the immune system to respond to pathogens would be highly desirable.…”