TY - JOUR
T1 - Interleukin-1 antagonists and other cytokine blockade strategies for type 1 diabetes
AU - Mandrup-Poulsen, Thomas
PY - 2012
Y1 - 2012
N2 - Proinflammatory cytokines stimulate adaptive immunity and attenuate T cell regulation and tolerance induction. They also profoundly impair β-cell function, proliferation, and viability, activities of similar importance in the context of type 1 diabetes (T1D). Detailed knowledge of the molecular mechanisms of β-cell toxicity has been gathered within the last 2-3 decades. However, the efficacy of individual proinflammatory cytokine blockade in animal models of T1D has been inconsistent and generally modest, except in the context of islet transplantation. This suggests that the timing of the cytokine blockade relative to anti-β-cell immune activation is critical, and that combination therapy may be required. In randomized, placebo-controlled, clinical trials of limited power, TNF-α (but not IL-1) blockade has yielded moderate but significant improvements in glycemia, insulin requirement, and β-cell function. The safety experience with anti-cytokine biologics is still very limited in T1D. However, combinations with other biologics, at doses of adaptive and innate immune inhibitors/modulators that are suboptimal or ineffective in themselves, may generate synergies of true therapeutic benefit and safety in T1D. Critical and balanced appraisal of the preclinical and clinical evidence of efficacy and safety of anti-immune, anti-inflammatory, and anti-dysmetabolic therapeutics should thus guide future studies to move closer to novel treatments, targeting the underlying causes of β-cell failure and destruction in T1D.
AB - Proinflammatory cytokines stimulate adaptive immunity and attenuate T cell regulation and tolerance induction. They also profoundly impair β-cell function, proliferation, and viability, activities of similar importance in the context of type 1 diabetes (T1D). Detailed knowledge of the molecular mechanisms of β-cell toxicity has been gathered within the last 2-3 decades. However, the efficacy of individual proinflammatory cytokine blockade in animal models of T1D has been inconsistent and generally modest, except in the context of islet transplantation. This suggests that the timing of the cytokine blockade relative to anti-β-cell immune activation is critical, and that combination therapy may be required. In randomized, placebo-controlled, clinical trials of limited power, TNF-α (but not IL-1) blockade has yielded moderate but significant improvements in glycemia, insulin requirement, and β-cell function. The safety experience with anti-cytokine biologics is still very limited in T1D. However, combinations with other biologics, at doses of adaptive and innate immune inhibitors/modulators that are suboptimal or ineffective in themselves, may generate synergies of true therapeutic benefit and safety in T1D. Critical and balanced appraisal of the preclinical and clinical evidence of efficacy and safety of anti-immune, anti-inflammatory, and anti-dysmetabolic therapeutics should thus guide future studies to move closer to novel treatments, targeting the underlying causes of β-cell failure and destruction in T1D.
KW - Animals
KW - Diabetes Mellitus, Type 1
KW - Humans
KW - Immunologic Factors
KW - Insulin-Secreting Cells
KW - Interleukin-1
KW - Tumor Necrosis Factor-alpha
U2 - 10.1900/RDS.2012.9.338
DO - 10.1900/RDS.2012.9.338
M3 - Journal article
C2 - 23804271
SN - 1613-6071
VL - 9
SP - 338
EP - 347
JO - The Review of Diabetic Studies
JF - The Review of Diabetic Studies
IS - 4
ER -
