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Rapamycin/IL-2 combination therapy in patients with type 1 diabetes augments Tregs yet transiently impairs β-cell

S Alice Long1, Mary Rieck, Srinath Sanda

  • 1Translational Immunology Program, Benaroya Research Institute, Seattle, Washington, USA. cgreenbaum@benaroyaresearch.org

Diabetes
|June 23, 2012
PubMed

Insights

Rapamycin and interleukin-2 (IL-2) combination therapy showed transient benefits for type 1 diabetes (T1D) in mice but caused temporary worsening in human patients. Immune changes, including increased regulatory T cells (Tregs), were observed, highlighting challenges in clinical translation.

Area of Science:

  • Immunology
  • Endocrinology
  • Clinical Trials

Background:

  • Autoimmune diabetes, or type 1 diabetes (T1D), is characterized by immune-mediated destruction of pancreatic beta cells.
  • Rapamycin and interleukin-2 (IL-2) combination therapy has shown promise in preclinical models of autoimmune diabetes.

Purpose of the Study:

  • To evaluate the safety and immunologic effects of a rapamycin/IL-2 combination therapy in patients with type 1 diabetes.
  • To assess the impact of this combination therapy on beta-cell function and immune cell populations.

Main Methods:

  • A phase 1 clinical trial involving nine T1D subjects.
  • Subjects received oral rapamycin (2-4 mg/day) for 3 months and subcutaneous IL-2 (4.5 × 10^6 IU) three times per week for 1 month.
  • Immunologic monitoring included flow cytometry and serum analyses; beta-cell function was assessed by C-peptide levels.

Main Results:

  • A transient increase in regulatory T cells (Tregs) was observed during IL-2 treatment.
  • Despite Treg increases, a transient worsening of clinical and metabolic parameters was noted in all subjects.
  • While Treg numbers normalized post-treatment, their IL-2 responsiveness (STAT5 phosphorylation) remained elevated.
  • Increases in natural killer cells and eosinophils were observed; effector T-cell subsets showed no significant changes.

Conclusions:

  • Rapamycin/IL-2 combination therapy resulted in transient beta-cell dysfunction in T1D patients, despite an increase in Tregs.
  • These findings underscore the complexities of translating preclinical therapies to clinical settings.
  • Comprehensive immune system interrogation is crucial for evaluating therapeutic effects in autoimmune diseases.

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