*Purpose: Transplantation of faces, hands, and limbs using vascularized composite allotransplantation (VCA) has faced significant challenges hindering its routine implementation in the clinic. One critical hurdle is the scarcity of adequately matched HLA donors, resulting in high doses of immunosuppressants which present significant risks to the patient. Alternative methods of controlling rejection are desperately needed. One possibility could be in exploiting the links between the nervous and immune systems that regulate host defense and responses to stress. The neurotransmitter norepinephrine regulates immune cells, acting via the β-adrenergic receptor (β₂-AR). Based upon data by our lab showing the role of β₂-AR signaling for decreasing graft-versus-host disease following bone marrow transplantation, we hypothesized that β₂-AR activation using the drug terbutaline would suppress immune cell function without the harmful side effects of toxic immunosuppressive drugs in the setting of HLA-mismatched VCA.

*Methods: Heterotopic hind limb transplantation mouse model of VCA was used with C57BL/6 (H-2b) as recipients and BALB/c (H-2d) mice as donors. Graft survival was tested with daily terbutaline injections. Different regimens of tacrolimus and terbutaline were investigated as a salvage treatment.

*Results: Even though terbutaline did not completely protect transplanted grafts from rejection there were fewer CD4⁺/8⁺ effector T cells infiltrating the graft site, delayed graft rejection, and lower histologic and gross rejection grades without severe side effects. A significant reduction was noted in IFNγ secreting CD4 T cells in the terbutaline group compared to the vehicle group. Additionally, in the salvage therapy tests terbutaline itself maintained grafts without severe rejection for a longer period than vehicle after stopping tacrolimus. Mechanistically, β-AR agonist inhibited T-cell activation by suppressing glucose uptake via GLUT1 channel delaying the immune response.

*Conclusions: Encouragingly, β₂-AR agonist could decrease doses of toxic immunosuppressive drugs to maintain healthy grafts, and may serve as a bridging therapy while recipients cannot take immunosuppressive drugs due to toxicities. Further investigations are needed to maximize the efficacy of β₂-AR agonist in transplant immunosuppression.

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