Low-dose infusion of a superagonistic anti-CD28 monoclonal antibody ameliorates inflammation after acute myocardial infarction in pigs

CD4+ Foxp3+ regulatory T cells (Treg) efficiently foster wound healing after myocardial infarction (MI). Moreover, therapeutic shifting of the balance between CD4+ Foxp3- conventional (Tconv) and Treg towards Treg enhances survival in mice after MI. Owing to the species-specific differences in cardiac wound healing and remodelling after MI, it remains unclear whether these findings can be translated into novel immunotherapies for patients with MI. Therefore, we tested the feasibility of therapeutic Treg activation after MI in pigs whose cardiac wound healing and the composition of the immune system are very close to humans. To activate Treg, we treated pigs three days after MI induction with a superagonistic anti-CD28 monoclonal antibody (mAb, CD28-SA; clone 4D12). To avoid induction of a cytokine release syndrome (CRS) we infused the CD28-SA at a low dose of 10 {micro}g/kg body weight. Low-dose CD28-SA treatment led to a local increase in porcine Treg among heart-infiltrating CD4+ T cells in comparison with the control mAb therapy (clone MOPC-21). Immunofluorescence histology showed that CD28-SA application particularly strengthened Treg accumulation in the infarct border zone. This was paralleled by a lower proportion of TNF-producing cells among cardiac monocytes and macrophages reflecting a shift away from inflammation and towards wound healing. Taken together, our findings in the pig MI model are the first to show that low-dose CD28-SA infusion is capable of ameliorating tissue inflammation in a species prone to CRS development after high-dose CD28-SA infusion. Moreover, the data highlight that therapeutically shifting the Treg/Tconv balance in MI patients might be feasible in order to enhance cardiac wound healing and prevent adverse remodelling.