bims-hummad 2024-09-22 papers

Issue of 2024‒09‒22
two papers selected by
Maksym V. Kopanitsa, Charles River Laboratories

Blood Adv. 2024 Sep 18. pii: bloodadvances.2022009187. [Epub ahead of print]

Targeting T cells with tetravalent bispecific antibodies for the treatment of graft versus host disease.

Madelyn Espinosa-Cotton, Sayed Shahabuddin Hoseini, Ileana C Miranda, John Herrick, Nai-Kong V Cheung.

Allogeneic hematopoietic stem cell transplantation is an established treatment for hematological malignancies and some genetic diseases. Acute graft versus host disease (GVHD) is the most common and debilitating side effect with poor survival rates of 5-30% for severe cases. In this manuscript, we describe a tetravalent T cell-engaging bispecific antibody (BsAb) based on the IgG-[L]-scFv platform, with all four binding domains specific for CD3. In vitro, picomolar concentrations of the CD3×CD3 BsAb induced potent lysis of activated CD4 and CD8 T cells. In immunodeficient mice, where human T cells induced xenogeneic GVHD, administration of 0.1 µg BsAb per dose depleted the majority of T cells from the peripheral blood, and 10 µg per dose completely reversed established GVHD and achieved a 100% survival rate. In mice bearing NALM6-luc xenografts, treatment with CD3×CD19 BsAb and activated human T cells induced complete remission of the leukemia and all treated mice developed GVHD by 50 days post-treatment. CD3×CD3 BsAb (3 to 30 µg doses) reversed clinical signs of GVHD, allowing long term followup beyond 250 days. T cells were undetectable by PCR in 4/5 mice in the 30 µg CD3×CD3 BsAb group 180 days after leukemia injection, and complete necropsies on day 259 revealed no evidence of human T cells or leukemia cells. Curing GVHD allows for long-term follow up of tumor response heretofore impossible in humanized mouse models. Further studies are warranted to determine if the CD3×CD3 BsAb has potential for treating clinical GVHD and other autoimmune diseases in humans.

DOI: https://doi.org/10.1182/bloodadvances.2022009187

Sci China Life Sci. 2024 Sep 13.

Reconstruction characteristics of gut microbiota from patients with type 1 diabetes affect the phenotypic reproducibility of glucose metabolism in mice.

Zhiyi Wang, Mengxue Gong, Yuanyuan Fang, Huijuan Yuan, Chenhong Zhang.

The human microbiota-associated (HMA) mice model, especially the germ-free (GF)-humanized mice, has been widely used to probe the causal relationships between gut microbiota and human diseases such as type 1 diabetes (T1D). However, most studies have not clarified the extent to which the reconstruction of the human donor microbiota in recipient mice correlates with corresponding phenotypic reproducibility. In this study, we transplanted fecal microbiota from five patients with T1D and four healthy people into GF mice, and microbiota from each donor were transplanted into 10 mice. Mice with similar microbiota structure to the donor exhibited better phenotypic reproducibility. The characteristics of the microbial community assembly of donors also influenced the phenotypic reproducibility in mice, and individuals with a higher proportion of stochastic processes showed more severe disorders. Microbes enriched in patients with T1D had a stronger colonization potential in mice with impaired glucose metabolism, and microbiota functional features related to T1D were better reproduced in these mice. This indicates that assembly traits and colonization efficacy of microbiota influence phenotypic reproducibility in GF-humanized mice. Our findings provide important insights for using HMA mice models to explore links between gut microbiota and human diseases.

Keywords: gut microbiome; human microbiota-associated animal model; type 1 diabetes

DOI: https://doi.org/10.1007/s11427-024-2658-1