The NBSGW RIP-DTR Mouse: An Integrated Platform for Diabetes Induction, Human Immune Reconstitution and Transplantation Studies

Chamberlain, C. S.; Kapadia, D.; Abad Santos, E.; Huang, L.; Holm, A.; Leavens, C.; Palwasha Khan, A.; Gorski, K. M.; Steck, C. C.; Mikat, A. S.; Tremmel, D. M.; Chlebeck, P.; Talerico, K.; Estrada, E.; McIntosh, B.; Brown, M. E.; Sackett, S. D.; Odorico, J. S.

doi:10.64898/2026.07.10.737744

bioRxiv · 10.64898/2026.07.10.737744

The NBSGW RIP-DTR Mouse: An Integrated Platform for Diabetes Induction, Human Immune Reconstitution and Transplantation Studies

Chamberlain, C. S.·Kapadia, D.·Abad Santos, E.·Huang, L.·Holm, A.·Leavens, C.·Palwasha Khan, A.·Gorski, K. M.·Steck, C. C.·Mikat, A. S.·Tremmel, D. M.·Chlebeck, P.·Talerico, K.·Estrada, E.·McIntosh, B.·Brown, M. E.·Sackett, S. D.·Odorico, J. S.

View original source ↗Export metadata ↓

Abstract

Using toxin receptor-mediated cell ablation, a diabetes mouse model was generated that supports engraftment of human hematopoietic stem/progenitor cells (HSPCs) without the need for irradiation. The NBSGW immunodeficient strain was crossed with the NSG RIP-DTR which carries the diphtheria toxin receptor (hDTR) under the control of the rat insulin promoter to generate the NBSGW RIP-DTR mouse. This model enables controlled {beta}-cell ablation, robust human immune system reconstitution without myeloablative conditioning, and evaluation of human immune-mediated graft rejection within a single platform. NBSGW RIP-DTR mice exhibited reproducible and titratable diabetes induction, supported durable human islet engraftment and glycemic correction, and retained efficient human hematopoietic reconstitution comparable to the parental NBSGW strain. In humanized mice, diphtheria toxin-mediated diabetes induction was well tolerated and enabled assessment of human immune responses to allogeneic islet grafts. Collectively, these findings establish the NBSGW RIP-DTR mouse as an integrated and clinically relevant platform for studying {beta}-cell replacement therapies and human immune-mediated graft rejection. Article HighlightsO_LICurrent preclinical models do not simultaneously support controlled diabetes induction, human islet transplantation, and durable human immune reconstitution without irradiation. C_LIO_LIThis study asked whether the NBSGW RIP-DTR mouse could integrate diphtheria toxin-mediated {beta}-cell ablation with irradiation-free humanization in a single platform. C_LIO_LINBSGW RIP-DTR mice demonstrated reproducible diabetes induction, supported functional human islet engraftment, and retained robust human hematopoietic reconstitution comparable to parental strains. C_LIO_LIThese findings establish the NBSGW RIP-DTR model as a clinically relevant platform for studying {beta}-cell replacement and human immune response to islet allografts, xenografts and stem cell-derived islets. C_LI

Explore related subjects

immunology Preprint

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

Chamberlain, C. S., Kapadia, D., Abad Santos, E., Huang, L., Holm, A., Leavens, C., Palwasha Khan, A., Gorski, K. M., Steck, C. C., Mikat, A. S., Tremmel, D. M., Chlebeck, P., Talerico, K., Estrada, E., McIntosh, B., Brown, M. E., Sackett, S. D., Odorico, J. S.. 2026-07-16. The NBSGW RIP-DTR Mouse: An Integrated Platform for Diabetes Induction, Human Immune Reconstitution and Transplantation Studies. https://doi.org/10.64898/2026.07.10.737744

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Common viral infections seed regionally distinct resident memory T cells in the human CNS

T cells persist in the central nervous system (CNS) and can drive both protection and neurological disease. How these cells are organized in humans and what they recognize is largely unknown. Here, we profiled CD8 T cells across anatomically distinct CNS regions, obtained through on-site autopsies and temporal lobe resection surgeries, using single-cell RNA sequencing, paired T cell receptor sequencing, and DNA-barcoded tetramers. Resident memory T cells (TRM) specific for Epstein-Barr virus, cytomegalovirus, influenza A, and SARS-CoV-2 were identified across CNS compartments. Anatomical location was the strongest correlate of TRM cell state, with leptomeningeal cells adopting a cytokine-poised TRM program, whereas brain TRM cells were transcriptionally restrained. Cells of the same clonotype spanned tissues yet adopted local transcriptional states. Viral specificity added another layer of TRM heterogeneity with GZMK/GZMA-expressing EBV-specific populations and interferon-stimulated gene signatures in SARS-CoV-2 and Influenza A-specific cells. The human CNS thus harbors regionally distinct CD8+ TRM shaped by common viral exposures.

immunology↗

bioRxiv2026

A regulatory T cell signature provides a shared molecular basis for the therapeutic window of opportunity in rheumatic disease

Rheumatic diseases, including rheumatoid arthritis (RA), spondyloarthritis (SpA) and osteoarthritis (OA), show distinct phenotypes yet respond to overlapping therapies, implicating shared immune mechanisms. In the Transimmunom cohort, we profiled peripheral blood from 240 individuals (47 healthy, 44 OA, 91 RA, 58 SpA) across deep immunophenotyping, immunoproteomics and Treg-Teff transcriptomics. Single-layer analyses revealed broader Treg than Teff remodeling, along with a shared pattern of reduced activated Tregs and expanded Helios+ Tregs across all diseases, alongside a decrease in functional Treg subpopulations, including CTLA4+ and CD45RA- Tregs. In RA specifically, LAG3+ Tregs were also expanded. Combining omics layers outperformed single-layer approaches for disease classification. Among individual layers, Treg transcriptomes were most discriminative, and integration uncovered disease-specific programs. Unsupervised clustering identified a cross-disease cluster independent of activity, treatment and age, mapping to early disease (<= years) and dominated by a Treg dysfunction-associated program. These results provide a biological rationale for the therapeutic "window of opportunity" concept and duration-stratified Treg-directed trials.

immunology↗

bioRxiv2026

Inhibitory Fc Receptor sets a time limit on macrophage response to IgG

Antibodies engage both activating Fc Receptors and the inhibitory receptor Fc{gamma}RIIB. Why macrophages need a dedicated inhibitory receptor rather than simply tuning activating receptor signaling is unclear. Using DNA-based chimeric receptors and in silico modeling, we independently controlled activating and inhibitory Fc Receptors. We found that Fc{gamma}RIIB imposed a time limit on macrophage phagocytosis and ERK signaling. The time limit is due to activating Fc Receptors converting PI(4,5)P2 to PI(3,4,5)P3, which is subsequently converted to PI(3,4)P2 by Fc{gamma}RIIB. This leads to a pulse of active signaling, which is sufficient for phagocytosis of small bacteria-sized targets but not phagocytosis of large targets and TNF secretion. Unlike engaging Fc{gamma}RIIB, reducing activating Fc Receptor signaling decreased initiation of phagocytosis, the speed of PI(3,4,5)P3 generation, and the amplitude of ERK signaling. Our results demonstrate that Fc{gamma}RIIB controls the duration of IgG signaling, while the activating Fc Receptors control sensitivity.

immunology↗