Sequential Immune Modulation and Antigen-Specific Tolerance Induction for Disease Modification in Recent-Onset Type 1 Diabetes

MATIN-2: Sequential Immune Modulation and Antigen-Specific Tolerance Induction for Disease Modification in Recent-Onset Type 1 Diabetes - A Mechanistic Framework and Phase I/II Protocol Proposal

This study tests a three-phase immune treatment for people recently diagnosed with Type 1 diabetes (within 6 months, with some insulin production remaining).

Phase 1 (weeks 1-2): Teplizumab, an anti-CD3 antibody, is given by infusion to slow immune attack on insulin-producing beta cells.

Phase 2 (months 2-9): Insulin is injected directly into a lymph node (intralymphatic immunotherapy, ILIT) alongside low-dose interleukin-2 to teach the immune system to tolerate insulin and expand protective regulatory T cells.

Phase 3 (months 10-24): Low-dose interleukin-2 is continued to maintain immune tolerance.

The main goal is to preserve the body's remaining insulin production (measured by C-peptide). Sixty adults aged 18-45 will be randomly assigned to the MATIN-2 protocol or standard care. Safety, immune markers, and HbA1c will also be monitored.

Inclusion Criteria:

• Age 18-45 years
• Clinical diagnosis of Type 1 diabetes mellitus within 6 months of enrolment
• Positive for at least one diabetes-related autoantibody (GAD65, IA-2, ZnT8, or IAA)
• Detectable fasting or stimulated C-peptide ≥ 0.2 nmol/L
• HbA1c ≤ 10% (86 mmol/mol)
• Ability to provide written informed consent

Exclusion Criteria:

• Prior immunosuppressive therapy within 3 months
• Active or chronic infection (HIV, hepatitis B/C, tuberculosis)
• Current or prior malignancy within 5 years (except non-melanoma skin cancer)
• Pregnancy or breastfeeding
• Severe renal impairment (eGFR < 30 mL/min/1.73m²)
• Severe hepatic impairment (Child-Pugh C)
• Known hypersensitivity to teplizumab or any excipient
• Participation in another interventional trial within 30 days
• Current systemic corticosteroid or immunomodulatory agent use
• History of other autoimmune disease requiring immunosuppression
• Absolute lymphocyte count < 1.0 × 10⁹/L
• ALT or AST > 3× upper limit of normal
• Haemoglobin < 100 g/L
• Unwillingness to use contraception during study period