Donor CD4 T cells trigger costimulation blockade-resistant donor bone marrow rejection through bystander activation...

Area of Science:

• Immunology
• Transplantation Biology

Background:

• Costimulation blockade normally induces bone marrow (BM) transplant tolerance.
• However, co-transplanting donor T cells with BM paradoxically causes rejection via unknown mechanisms.

Purpose of the Study:

• To elucidate the mechanisms by which donor T cells induce BM rejection under costimulation blockade.
• To identify therapeutic targets for preventing T cell-mediated BM rejection.

Main Methods:

• Nonmyeloablative BM transplantation in mice with simultaneous donor T cell co-administration under costimulation blockade (anti-CD154 and CTLA4Ig).
• Investigated the role of CD4+ vs. CD8+ T cells, cytokine production (IL-6, IFN-γ, IL-17A), and therapeutic interventions (cytokine neutralization, rapamycin, anti-LFA-1).

Main Results:

• Donor CD4+ T cells, but not CD8+ T cells, triggered BM rejection, associated with increased IL-6, IFN-γ, and IL-17A.
• IL-6 neutralization prevented rejection; IL-6 counteracted anti-CD154's antiproliferative effect.
• Rapamycin and anti-LFA-1 inhibited IL-6's effect in vitro and prevented rejection in vivo.

Conclusions:

• Donor T cells recognizing recipient alloantigens release IL-6, overriding costimulation blockade and causing BM rejection.
• IL-6 is a key mediator of T cell-induced BM rejection, and targeting IL-6 or related pathways offers therapeutic potential.