Biology subjects

Beyersdorf, N.

Publications and source records attributed to Beyersdorf, N..

3 recordsLinked to original sources

bioRxiv2026

Treatment with saturating dose of conventional anti-CD28 monoclonal antibody well tolerated in pig acute myocardial infarction model

CD4+ Foxp3+ regulatory T cells (Treg) efficiently foster wound healing after myocardial infarction (MI). Therapeutically shifting the balance between CD4+ Foxp3- conventional T cells (Tconv) and Treg towards Tregs enhanced survival in a mouse model of MI. Due to species-specific differences in cardiac wound healing and remodelling, it remains, however, unclear whether these findings can be translated into novel immunotherapies for human patients after MI. Therefore, we studied pigs whose cardiac wound healing after MI and the composition of the immune system are very close to humans. This includes the relevant complication of developing a cytokine release syndrome (CRS) after infusion of saturating amounts of a superagonistic anti-CD28 monoclonal antibody (mAb). To achieve the intended shift in the Treg/Tconv balance, we treated pigs three days after interventional MI induction with a non-superagonistic, i.e. conventional, anti-CD28 mAb, clone 3D11. Infusion of a saturating dose (1 mg/kg body weight) of mAb 3D11 was clinically well tolerated without signs of CRS induction or any other complications. Molecularly, mAb 3D11 infusion led to a downmodulation of CD28 expression on porcine T cells in vivo with the remaining CD28 molecules blocked from binding natural ligand proteins CD80 and CD86, as we show in this publication. Apart from modulating CD28 expression, treatment with mAb 3D11 did not induce any overt changes in the peripheral T cell compartment. However, after mAb 3D11 treatment, we observed Treg accumulation in the infarcted heart, particularly the border zone, on day 7 post-MI using immunofluorescence histology. Our findings thus suggest that even saturating doses of conventional anti-CD28 monoclonal antibodies could potentially be safely administered in patients to therapeutically shift the Treg/Tconv balance in the infarcted myocardium. This might be sufficient to enhance cardiac wound healing in patients short-term and prevent adverse remodelling long-term.

immunology↗

bioRxiv2025

Changes in peripheral blood leukocyte composition precede development of heart-reactive autoantibodies in patients hospitalised for acute heart failure

In a retrospective pilot study, we showed that the induction of heart-reactive autoantibodies (HRA) in the wake of acutely decompensated heart failure predicts worse outcomes. To gain deeper insights into the immunological mechanisms causing induction of HRA after heart failure decompensation we initiated the prospective Acute Heart Failure-Immunomonitoring Cohort Study (AHF-ImmunoCS). For this study, 380 patients were enrolled and will be followed up, including serial collection of biomaterials, for a period of 18 months after the index hospitalisation for AHF. Analysis of AHF-ImmunoCS samples obtained at baseline and at 6-month follow-up from 110 patients showed de novo induction of HRA - as detected by indirect immunofluorescence (IFT) - in 21% of patients (previously published percentage: 32%). The IFT results did not reflect induction of broad anti-heart autoimmunity as autoantibodies against other cardiac antigens like Troponin I3 or Myosin Light Chain 7 were not induced in parallel. To understand what drives HRA induction in these patients we longitudinally immunophenotyped peripheral blood leukocytes at baseline, 6-week and 6-month follow-up by high-resolution spectral flow cytometry. Among lymphocytes, induction of HRA in the wake of acute decompensation of heart failure was associated with a higher proportion of CD4+ T cells among lymphocytes, more CD45RA+ CCR7+ naive conventional, i.e. non-regulatory, and more CXCR3+ CCR4- Th1 cells among CD4+ T cells at baseline. Among myeloid cells, there were no differences at baseline between patients going on to develop HRA and those that did not. However, patients developing HRA had higher proportions of eosinophils (six-month follow-up) and lower proportions of Arginase+ HLA-DR- polymorphnuclear myeloid-derived suppressor cells among myeloid cells (six-week and six-month follow-up). Our data, thus, implicate that alterations in the composition of both the lymphoid and the myeloid compartments might drive HRA induction which impacts disease progression and prognosis in AHF.

immunology↗

bioRxiv2025

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.

immunology↗