Complement Dependence of Murine Costimulatory Blockade-Resistant Cellular Cardiac Allograft Rejection

Area of Science:

• Immunology
• Transplantation Biology
• Complement System

Background:

• Ischemia-reperfusion (I/R) injury is a significant factor in organ transplant rejection.
• Complement activation has been implicated in I/R injury, but its specific role in allograft rejection remains to be fully elucidated.

Purpose of the Study:

• To investigate the role of complement activation, specifically the mannose-binding lectin (MBL) pathway, in cardiac allograft rejection following I/R injury.
• To evaluate the therapeutic potential of inhibiting the complement system, using C1 inhibitor (C1-INH), in preventing transplant rejection.

Main Methods:

• Cardiac transplantation in mice with varying complement deficiencies (C3-/-, MBL-/-, Factor B-/-).
• Treatment with cytotoxic T-lymphocyte associated protein 4 (CTLA4)Ig and C1 inhibitor (C1-INH).
• Assessment of graft survival, chemokine/cytokine induction, and T cell responses (priming, expansion, and interferon-γ production).

Main Results:

• Recipient C3 deficiency significantly prolonged cardiac allograft survival (>60 days) compared to wild-type recipients (37 days).
• Graft survival was significantly longer in MBL-deficient mice (>60 days) than in Factor B-deficient mice (42 days), implicating the MBL pathway.
• Peritransplantation administration of C1-INH prolonged graft survival (>60 days) and reduced donor-reactive T cell responses.

Conclusions:

• The MBL-initiated complement pathway plays a critical role in linking I/R injury to T cell-mediated cardiac allograft rejection.
• C1-INH administration is a promising therapeutic strategy to prevent complement-mediated allograft rejection, even in cases resistant to CTLA4Ig therapy.