Chawda, Mira Manilal; (2023) Investigation of Athymia and Immune Reconstitution in Mouse Models. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

CHARGE syndrome and DiGeorge syndrome (DGS) are multiorgan congenital disorders, with overlapping phenotypes, including athymia causing immunodeficiency, a life-threatening condition. One treatment for athymia is thymus transplantation. Thymus tissue is cultured for three weeks to deplete thymocytes before transplantation, which delays treatment, and donor tissue is not MHC-matched. Thymocytes are sensitive to freezing, so cryopreservation could be used to preserve thymic epithelial cells (TEC) selectively as the cell type of importance in thymus transplant, whilst depleting thymocytes. Using mouse foetal thymic organ cultures, we showed that cryopreservation significantly depleted thymocytes compared to non-cryopreserved lobes (NCPL). We next performed in vivo thymus transplants of cryopreserved donor GFP+ (Green Fluorescent Protein) thymic lobes into nude mice. We found that donor depletion of GFP+CD4+ and GFP+CD8+ T-cells for the cryopreserved lobe (CPL) was equivalent to that of the NCPL. T-cell reconstitution by host progenitor cells that developed in the transplanted thymus lobes, showed similar levels for CPL and NCPL. We concluded, that although cryopreservation did not significantly increase donor T-cell depletion, it supported recipient T-cell development as efficiently as NCPL, so tissue can be processed for biobanking and MHCmatching for use in future patient transplants, as its function is maintained. The gene responsible for CHARGE syndrome is CHD7, which functions as a chromatin remodeler. The TBX1 gene encodes a transcription factor that regulates embryonic development and has been linked to DGS. We used mouse models to investigate Chd7 and Tbx1 function in the thymus. Conditional deletion of Chd7 from thymocytes impacted early T-cell development. However, conditional deletion of Chd7 and/or Tbx1 from TEC had no influence on T-cell development, indicating that the immunodeficiency experienced by CHARGE syndrome and DGS patients is unlikely to be the result of a requirement for these proteins in adult TEC.

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