PT  - JOURNAL ARTICLE
AU  - Goor, Alona
AU  - Altman, Efrat
AU  - Arman, Inbar
AU  - Erez, Shir
AU  - Haus-Cohen, Maya
AU  - Reiter, Yoram
TI  - Antigen-specific modulation of chronic experimental autoimmune encephalomyelitis in humanized mice by TCR-like antibody targeting autoreactive T-cell epitope
AID  - 10.26508/lsa.202402996
DP  - 2025 Jan 01
TA  - Life Science Alliance
PG  - e202402996
VI  - 8
IP  - 1
4099  - https://www.life-science-alliance.org/content/8/1/e202402996.short
4100  - https://www.life-science-alliance.org/content/8/1/e202402996.full
SO  - Life Sci. Alliance2025 Jan 01; 8
AB  - The development and application of human TCR-like (TCRL) antibodies recognizing disease-specific MHC–peptide complexes may prove as an important tool for basic research and therapeutic applications. Multiple sclerosis is characterized by aberrant CD4 T-cell response to self-antigens presented by MHC class II molecules. This led us to select a panel of TCRL Abs targeting the immunodominant autoantigenic epitope MOG35-55 derived from myelin oligodendrocyte glycoprotein (MOG) presented on HLA-DR2, which is associated with multiple sclerosis (MS). We demonstrate that these TCRL Abs bind with high specificity to human HLA-DR2/MOG35-55-derived MHC class II molecules and can detect APCs that naturally present the MS-associated autoantigen in the humanized EAE transgenic mouse model. The TCRL Abs can block ex vivo and in vivo CD4 T-cell proliferation in response to MOG35-55 stimulation in an antigen-specific manner. Most significantly, administration of TCRL Abs to MOG35-55-induced EAE model in HLA-DR2 transgenic mice both prevents and regresses established EAE. TCRL function was associated with a reduction in autoreactive pathogenic T-cell infiltration into the CNS, along with modulation of activated CD11b+ macrophages/microglial APCs. Collectively, these findings demonstrate the combined action of TCRL Abs in blocking TCR-MHC interactions and modulating APC presentation and activation, leading to a profound antigen-specific inhibitory effect on the neuroinflammatory process, resulting in regression of EAE. Our study constitutes an in vivo proof of concept for the utility of TCR-like antibodies as antigen-specific immunomodulators for CD4-mediated autoimmune diseases such as MS, validating the importance of the TCR-MHC axis as a therapeutic target for various autoimmune and inflammatory diseases.