Biology subjects

Gladow, N.

Publications and source records attributed to Gladow, 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

CD4+ T cells fuel the Duchenne cardiomyopathy

Duchenne muscular dystrophy (DMD) is a X-linked genetic disorder, in which cardiomyopathy represents a major cause of mortality. Although myocardial inflammation and fibrosis are hallmarks of the disease, the role of adaptive immunity in cardiac pathology remains poorly defined. Using the Mdx mouse model, we demonstrate that T and B lymphocytes accumulate in the heart and that activation occurs in heart-draining lymph nodes at an early disease stage. Mdx mice lacking adaptive immunity (Mdx-Scid) were protected from myocardial fibrosis and hypertrophic remodeling. Single-cell RNA sequencing revealed expansion of an inflammatory, matrisome-associated macrophage subset in Mdx but not Mdx-Scid hearts. Genetic deficiency or depletion of CD4+ T cells reduced left ventricular fibrosis and preserved systolic function. Moreover, adoptive transfer of T cells von Mdx mice induced myocardial fibrosis and dysfunction in healthy recipients. Our results identify autoreactive CD4+ T cells as key drivers of DMD-associated cardiomyopathy and suggest targeted modulation of adaptive immune responses as a potential therapeutic approach in DMD.

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↗