Progress in the development of immune-based therapies for type 1 diabetes mellitus.
Between ten and twenty million people worldwide have type 1 diabetes mellitus (T1DM), which has previously been called juvenile diabetes, childhood diabetes, and insulin-dependent diabetes mellitus. T1DM is undoubtedly a multifactorial disease affecting predisposed individuals with genetic susceptibilities; it is also associated with environmental factors leading to unbalanced immune responses. This chronic disorder is caused by auto-aggressive T lymphocytes entering the pancreatic islets of Langerhans where they destroy the insulin-producing beta-cells. A wide variety of immuno-interventions cure T1DM effectively in different animal models when given early in disease development. However, few of these interventions are efficacious in humans at a later stage of the disease. Indeed, only three immunotherapeutic compounds have demonstrated both safety and efficacy in phase II/III clinical trials. Although much time and resources have been spent on generating potent immune therapies, none of the patients enrolled in these trials have achieved normoglycemia in the absence of insulin injections. Many reasons can account for such a disappointing conclusion. Firstly, the dynamics of disease pathogenesis differs significantly from patient to patient, which directly impacts the therapeutic efficacy. Also, at trial entry, the percentage of remaining pancreatic beta-cells in T1DM patients often reflects the odds of responding positively to treatment. Based on the knowledge we have gained from preclinical studies and clinical trials, several steps have been made in the development of safer and more efficient immune-based therapies. There are, however, a number of concerns that should be addressed in order to improve future therapeutic strategies.
von Herrath
Matthias
M
Department of Developmental Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, California 92037, USA.
Rottembourg
Diane
D
Bresson
Damien
D
D000818:Animals; D000941:Antigens / Q000276:immunology; D015551:Autoimmunity / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D018450:Disease Progression; D006801:Humans; D007167:Immunotherapy / Q000639:trends*
D000941:Antigens