Otelixizumab in the Treatment of Type 1 Diabetes Mellitus
Otelixizumab in the Treatment of Type 1 Diabetes Mellitus
Type 1 diabetes is an autoimmune disease, characterized by an immune-mediated destruction of the insulin-secreting β-cells within the pancreatic islets of Langerhans. The progressively declining β-cell mass severely compromises insulin secretion and glycemic control, ultimately driving clinical manifestation of disease when glucose concentrations can no longer be maintained within the physiological range. Up to now, life-long insulin replacement is the standard therapy to control the acute symptoms of Type 1 diabetes, including hyperglycemia and subsequent polyuria and polydipsia. However, as a chronic state of mild hyperglycemia often persists, long-term complications, such as retinopathy, nephropathy, neuropathy and micro-angiopathy, cannot be fully prevented by this treatment regimen, emphasizing the need for novel therapies that can revert or at least halt disease progression.
Type 1 diabetes is, by contrast to the epidemic prevalence of Type 2 diabetes, a rare disease, with less than 10% of all diabetics suffering from Type 1. However, Type 1 diabetes is the most prevelant form under the age of 40 years. During the last decades, a rapid increase in Type 1 diabetes prevalence in young children has been observed, indicating a more aggressive presentation of the disease. At present, an estimated 3 million people suffer from Type 1 diabetes in Europe. In spite of extensive research, the etiological factors underlying the Type 1 diabetes development remain obscure, but both genetic and environmental factors are proposed to contribute to disease risk. Much attention is given to the identification of the environmental triggers that might contribute to the breakdown of immunological tolerance against pancreatic β-cells and subsequent Type 1 diabetes development in genetically predisposed individuals. Up to now, multiple environmental risk determinants have been proposed to influence disease risk; including viral infections, early infant diet, toxins, vaccine administration, climate influences and many others, but none of these were found to be exclusively attributable for the initiation of disease. Therefore, particular efforts are made to increase the current knowledge on the immunological processes underlying Type 1 diabetes initiation and subsequent disease progression, as identification of the central cellular players and molecular pathways will provide new targets for the development of effective therapies to prevent, halt or reverse Type 1 diabetes development. Limited access to human pancreatic tissue obstructs the study of human Type 1 diabetes. Therefore, most of the current knowledge on Type 1 diabetes development has been gathered by the use of animal models. In particular, the nonobese diabetic (NOD) mouse model represents an important source of information, not only providing crucial information on Type 1 diabetes pathogenesis, but also unveiling important insights on the mechanisms of immunoregulation and tolerance.
Type 1 diabetes is classified as a T-cell-mediated disease. Indeed, both CD4 and CD8 T cells are abundantly present within the histopathological lesion. Of note, whereas T cells are generally regarded as the central mediators of β-cell destruction, these cells also mount protective responses during the disease course, which specifically rely on the actions of Tregs. Given the primary role of T cells in the pathogenesis of Type 1 diabetes, T-cell-directed therapies are of great interest to prevent or halt the autoimmune processes underlying β-cell destruction. Mostly using the NOD mouse as a preclinical screening model, a wide array of approaches to modulate T-cell responses have been explored, including the use of T-cell depleting agents, molecules interfering with T-cell receptor (TCR) signaling, T-cell trafficking or adhesion, as well as compounds targeting costimulatory molecules, cytokines or cytokine signaling. As such, the list of therapeutics capable of preventing Type 1 diabetes development has dramatically expanded throughout the years, with a general tendency for a higher success rate when interfering early in the disease course. However, from a clinical perspective, strategies able to reverse overt diabetes are of primary interest, as Type 1 diabetes is most commonly diagnosed upon presentation of clinical symptoms. Although more scarce as compared with preventive strategies, a limited number of agents could successfully reverse diabetes in animal models after clinical manifestation of the disease.
The current excellent safety profile of diabetes management by means of insulin supplementation sets the safety bar very high for any potential novel therapy to intervene in Type 1 diabetes. For this particular reason, the therapeutic efficacy of only a limited number of T-cell-directed therapies has eventually been tested in human diabetic subjects. Cyclosporine A (CsA) was the first agent for which the results obtained in animal models could be translated into humans. The use of this agent in randomized clinical studies demonstrated that CsA could successfully revert recent-onset diabetes, but the need for lifelong administration in order to maintain the therapeutic effects, as well as the strong nephrotoxic potential of this compound represented major pitfalls, eventually ruling out its further use for the treatment of Type 1 diabetes. Nevertheless, the results obtained with CsA represented an important milestone in Type 1 diabetes research, as it was demonstrated for the first time that T-cell-directed immunotherapy could indeed alter the disease course, providing a proof-of-concept for the suspected role of T cells in this disease. Owing to toxicity issues, other immunosuppressive regimens, such as the combined use of steroids and azathioprine, an inhibitor of lymphocyte proliferation, were equally excluded for future use, but yielded similar conclusions regarding the immune-related nature of the disease. In the meantime, several immunomodulatory interventions have taken place, some targeting specific members of the immune system, like anti-CD20 antibodies, with others attempting more general immunomodulation. To this day, no intervention has demonstrated a sustained β-cell protective effect, but the most promising data have been gathered with antibodies targeting CD3 molecules on the surface of T lymphocytes.
Interventions in Type 1 Diabetes
Type 1 diabetes is an autoimmune disease, characterized by an immune-mediated destruction of the insulin-secreting β-cells within the pancreatic islets of Langerhans. The progressively declining β-cell mass severely compromises insulin secretion and glycemic control, ultimately driving clinical manifestation of disease when glucose concentrations can no longer be maintained within the physiological range. Up to now, life-long insulin replacement is the standard therapy to control the acute symptoms of Type 1 diabetes, including hyperglycemia and subsequent polyuria and polydipsia. However, as a chronic state of mild hyperglycemia often persists, long-term complications, such as retinopathy, nephropathy, neuropathy and micro-angiopathy, cannot be fully prevented by this treatment regimen, emphasizing the need for novel therapies that can revert or at least halt disease progression.
Type 1 diabetes is, by contrast to the epidemic prevalence of Type 2 diabetes, a rare disease, with less than 10% of all diabetics suffering from Type 1. However, Type 1 diabetes is the most prevelant form under the age of 40 years. During the last decades, a rapid increase in Type 1 diabetes prevalence in young children has been observed, indicating a more aggressive presentation of the disease. At present, an estimated 3 million people suffer from Type 1 diabetes in Europe. In spite of extensive research, the etiological factors underlying the Type 1 diabetes development remain obscure, but both genetic and environmental factors are proposed to contribute to disease risk. Much attention is given to the identification of the environmental triggers that might contribute to the breakdown of immunological tolerance against pancreatic β-cells and subsequent Type 1 diabetes development in genetically predisposed individuals. Up to now, multiple environmental risk determinants have been proposed to influence disease risk; including viral infections, early infant diet, toxins, vaccine administration, climate influences and many others, but none of these were found to be exclusively attributable for the initiation of disease. Therefore, particular efforts are made to increase the current knowledge on the immunological processes underlying Type 1 diabetes initiation and subsequent disease progression, as identification of the central cellular players and molecular pathways will provide new targets for the development of effective therapies to prevent, halt or reverse Type 1 diabetes development. Limited access to human pancreatic tissue obstructs the study of human Type 1 diabetes. Therefore, most of the current knowledge on Type 1 diabetes development has been gathered by the use of animal models. In particular, the nonobese diabetic (NOD) mouse model represents an important source of information, not only providing crucial information on Type 1 diabetes pathogenesis, but also unveiling important insights on the mechanisms of immunoregulation and tolerance.
Type 1 diabetes is classified as a T-cell-mediated disease. Indeed, both CD4 and CD8 T cells are abundantly present within the histopathological lesion. Of note, whereas T cells are generally regarded as the central mediators of β-cell destruction, these cells also mount protective responses during the disease course, which specifically rely on the actions of Tregs. Given the primary role of T cells in the pathogenesis of Type 1 diabetes, T-cell-directed therapies are of great interest to prevent or halt the autoimmune processes underlying β-cell destruction. Mostly using the NOD mouse as a preclinical screening model, a wide array of approaches to modulate T-cell responses have been explored, including the use of T-cell depleting agents, molecules interfering with T-cell receptor (TCR) signaling, T-cell trafficking or adhesion, as well as compounds targeting costimulatory molecules, cytokines or cytokine signaling. As such, the list of therapeutics capable of preventing Type 1 diabetes development has dramatically expanded throughout the years, with a general tendency for a higher success rate when interfering early in the disease course. However, from a clinical perspective, strategies able to reverse overt diabetes are of primary interest, as Type 1 diabetes is most commonly diagnosed upon presentation of clinical symptoms. Although more scarce as compared with preventive strategies, a limited number of agents could successfully reverse diabetes in animal models after clinical manifestation of the disease.
The current excellent safety profile of diabetes management by means of insulin supplementation sets the safety bar very high for any potential novel therapy to intervene in Type 1 diabetes. For this particular reason, the therapeutic efficacy of only a limited number of T-cell-directed therapies has eventually been tested in human diabetic subjects. Cyclosporine A (CsA) was the first agent for which the results obtained in animal models could be translated into humans. The use of this agent in randomized clinical studies demonstrated that CsA could successfully revert recent-onset diabetes, but the need for lifelong administration in order to maintain the therapeutic effects, as well as the strong nephrotoxic potential of this compound represented major pitfalls, eventually ruling out its further use for the treatment of Type 1 diabetes. Nevertheless, the results obtained with CsA represented an important milestone in Type 1 diabetes research, as it was demonstrated for the first time that T-cell-directed immunotherapy could indeed alter the disease course, providing a proof-of-concept for the suspected role of T cells in this disease. Owing to toxicity issues, other immunosuppressive regimens, such as the combined use of steroids and azathioprine, an inhibitor of lymphocyte proliferation, were equally excluded for future use, but yielded similar conclusions regarding the immune-related nature of the disease. In the meantime, several immunomodulatory interventions have taken place, some targeting specific members of the immune system, like anti-CD20 antibodies, with others attempting more general immunomodulation. To this day, no intervention has demonstrated a sustained β-cell protective effect, but the most promising data have been gathered with antibodies targeting CD3 molecules on the surface of T lymphocytes.
Source...