bims-hummad 2025-11-02 papers

Clin Sci (Lond). 2025 Oct 28. pii: CS20257272. [Epub ahead of print]139(21):

Low- and high-dose post-transplant cyclophosphamide attenuates graft-versus-host disease with distinct effects on PD-1+ T cell subsets.

Chloe Sligar, Miles J Jacobs, Amal Elhage, Ronald Sluyter, Debbie Watson.

Allogeneic haematopoietic stem cell transplantation (alloHSCT) is a curative treatment for haematological malignancies. AlloHSCT aims to generate graft-versus-leukaemia immunity, where donor T cells eliminate residual malignant cells. However, graft-versus-host disease (GVHD), where donor T cells attack recipient tissues, is a common and often fatal side effect. Post-transplant cyclophosphamide (PTCy) can reduce GVHD, but the cellular mechanisms through which this occurs are not fully understood, and high doses may be associated with toxicity. This study aimed to determine whether lower doses of PTCy can reduce GVHD and to examine the effects of PTCy doses on human (h) immune cell subsets, T cell exhaustion, and histological GVHD in a humanised mouse model. NOD-scid-IL2Rγnull mice were injected with 2 × 107 human peripheral blood mononuclear cells on day 0, cyclophosphamide (10, 25 or 33 mg/kg) or control diluent on days 3 and 4 and monitored for GVHD development at early and late time points. Low-dose PTCy (10 mg/kg) abrogated clinical signs of GVHD with comparable efficacy to high-dose PTCy (33 mg/kg), delaying GVHD onset and prolonging mouse survival. Proportions of hPD-1+ hCD4+ and hPD-1+hCD8+ T cells were increased with low-dose PTCy but not higher doses, while hPD-1+ hTreg proportions were increased by all PTCy doses. Exhausted hPD-1+hLAG3+hCD8+ T cell proportions were increased with high-dose PTCy, but not lower doses. This study indicates that low-dose PTCy reduces GVHD with similar efficacy to that of high-dose PTCy, but this appears to be associated with differing cellular mechanisms of action.

Keywords: T cell exhaustion; humanised mice; post-transplant cyclophosphamide; xenogeneic graft-versus-host disease

DOI: https://doi.org/10.1042/CS20257272

Front Immunol. 2025 ;16 1640611

Inhibition of CD38 enzyme activity on engrafted human immune cells enhances NAD+ metabolism and inhibits inflammation in an in-vivo model of xeno-GvHD.

Ghenima Ahmil-Boiteau, Pranjali Dalvi, Kevin Dang, Harshad S Ugamraj, Giulia Castello, James Allison, Ute Schellenberger, Roland Buelow, Suhasini Iyer, Ben Buelow, Eduardo Chini, Bruce Blazar, Maria Cristina Cuturi, Wim van Schooten, Laure-Hélène Ouisse.

Introduction: CD38 is highly expressed on immune cells. It catabolizes NAD+, which is a critical cofactor for enzymes involved in metabolism and energy production.
Methods and results: We developed TNB-738, a fully human antibody that potently inhibits human CD38 enzymatic activity on human immune cells, resulting in a dose-dependent increase of intracellular NAD+ levels. TNB-738 does not show immune effector functions, does not induce direct cell killing of CD38 positive cells and is not internalized. In vivo, treatment with TNB-738 following infusion of human PBMCs into NSG mice resulted in significantly lower clinical scores, prolonged overall survival, less expansion of engrafted human CD45+ cells and a significant expansion of Tregs.
Discussion: CD38 positive T cells regulate NAD+ metabolism in inflamed tissues and blockade of CD38 enzyme activity by TNB-738 could represent a novel class of therapeutics for the treatment of inflammatory conditions, including GvHD.

Keywords: CD38; GvHD; NAD+; TNB-738; inflammation

DOI: https://doi.org/10.3389/fimmu.2025.1640611

Mol Ther. 2025 Oct 30. pii: S1525-0016(25)00932-3. [Epub ahead of print]

First-in-class anti-human CD45RC antibody targets CD45RChigh T and B cells to mitigate pathogenic immune responses.

Cécile Bergua, Ghenima Ahmil-Boiteau, Laure-Hélène Ouisse, Nadège Vimond, Céline Sérazin, Lisa Dugast, Romain Humeau, Apolline Salama, Laurent Tesson, Katleen Swinnen, Ronald Van Brempt, Alexis Collette, Ignacio Anegon, Carole Guillonneau.

CD45RC, an isoform of the transmembrane tyrosine phosphatase CD45, regulates T and B cell antigen receptor signaling and is highly expressed on Th1 precursor, Th1 cells, T effector memory CD45RA+ cells and most B cells. Preclinical studies have shown that anti-CD45RC monoclonal antibodies can prevent or control diseases such as transplant rejection, graft-versus-host disease, Duchenne muscular dystrophy, and APECED. However, their mechanism of action remained unclear. Here, we elucidate the mechanism of anti-human CD45RC mAbs, showing that it selectively induces apoptosis in CD45RChigh T and B cells through binding to cells expressing >24 CD45RC molecules/μm2. This interaction triggers intracellular signaling without cytokine release. Cytotoxicity by apoptosis is enhanced by crosslinking with a secondary antibody. The mAb also promotes antibody-dependent cellular phagocytosis by monocyte-derived macrophages, without inducing antibody-dependent cellular cytotoxicity or complement-dependent cytotoxicity, likely due to the length of CD45RC. In CD34+-humanized NSG mice, anti-CD45RC mAb demonstrated dose-dependent depletion of CD45RChigh T and B cells and defined a minimal effective dose to prevent xenogeneic GvHD. These findings define the mechanism of action of this first-in-class anti-human CD45RC therapeutic mAb and supports its potential for the treatment of transplant rejection, GvHD and autoimmune diseases.

DOI: https://doi.org/10.1016/j.ymthe.2025.10.057