Abstract
Pre-clinical murine models are critical for translating drug candidates from the bench to the bedside. There is interest in better understanding how anti-human CD3 therapy works based on recent longitudinal studies of short-term administration. Although several models have been created in this pursuit, each have their own advantages and disadvantages in Type-1 diabetes. In this study, we report a murine genetic knock-in model which expresses both a murine and a humanized-CD3ε-exon, rendering it sensitive to manipulation with anti-human CD3. These huCD3εHET mice are viable and display no gross abnormalities. Specifically, thymocyte development and T cell peripheral homeostasis is unaffected. We tested immune functionality of these mice by immunizing them with T cell-dependent antigens and no differences in antibody titers compared to wild type mice were recorded. Finally, we performed a graft-vs-host disease model that is driven by effector T cell responses and observed a wasting disease upon transfer of huCD3εHET T cells. Our results show a viable humanized CD3 murine model that develops normally, is functionally engaged by anti-human CD3 and can instruct on pre-clinical tests of anti-human CD3 antibodies.
Highlights
Monoclonal antibodies are versatile biologic agents known to improve outcomes in autoimmune, transplant rejection and malignant diseases
We identified several alterations in the T cell phenotype of huCD3εHOM mice, making these mice unsuitable to serve as a surrogate mouse model to test the effect of anti-human CD3 antibodies on biology
Taking the results from both in vivo models together, we show that huCD3εHET T cell responses are unimpaired and T cells are able to perform their effector functions making this model suitable to further test pre-clinically the effect of anti-human CD3 therapy in different models of disease in the C57BL/6 background
Summary
Monoclonal antibodies are versatile biologic agents known to improve outcomes in autoimmune, transplant rejection and malignant diseases. These may work in a variety of ways, for example by 1) dampening inflammatory immune or cellular responses [1,2,3,4], 2) activating the immune response [5,6,7], or 3) inducing a state of immune tolerance [8,9,10]. Monoclonal antibodies to CD3 have been used in the clinic to help in organ transplantation and treat autoimmune diseases with varying degrees of success. Patients have received antiCD3 therapy to suppress acute graft-rejection or acute renal failure following kidney
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
