An investigation of regulatory T cell therapy in advanced human skin experimental transplantation models

Thesis

Regulatory T cells (Tregs) are powerful suppressors of immune responses and help preserve immune homeostasis and self-tolerance. Specific Treg subsets—including those expressing the chemokine receptors CCR4 and CCR8—demonstrate high suppressive potency in certain clinical contexts. Several studies have revealed the promise of Treg cellular therapies in counteracting immune-mediated pathologies including transplant rejection. Clinical translation of Treg therapies must be supported by ongoing pre-clinical and clinical research to both evidence and enhance its safety and efficacy.

Humanised experimental mice provide a cost-effective and practical approach to create in vivo models for pre-clinical transplant research. However, issues including high technical demand and variable capacities to represent human biology can limit their use.

The two aims of this study were to develop an advanced humanised mouse model that could support multilineage human haematopoeisis and accurately represent human allotransplantation, and to investigate whether specific skin-homing human Treg subsets can provide effective anti-rejection therapy for skin allografts.

In the first part of this study, HSPC-NBSGW mice—non-irradiated NOD,B6.SCID IL-2rγ-/-KitW41/W41 (NBSGW) mice engrafted with human CD133+ hematopoietic stem and progenitor cells (HSPCs)—were assessed for function capability in the context of allotransplantation. In depth characterisation of durable human haematopoeitic cell engraftment was followed by quantitative transcriptomic and immunophenotypic analyses of complete skin allograft rejection, which this model can effect through functional human innate and adaptive immune cells.

In the second part, the suppressive capabilities of chemokine receptor-expressing Tregs were evaluated phenotypically and functionally. In addition to potent immune suppression mediated by CCR4-expressing Tregs, subcutaneous CCL22 administration in the presence of Treg therapy prevented skin allograft rejection.

As the potential of Treg therapy has become clearer, pre-clinical research is becoming an increasingly essential tool for uncovering features of Treg behaviour and function that may help optimise safety and efficacy. The findings presented in this thesis advance the in vivo research toolkit and describe an additional method by which Tregs may be manipulated to enhance their therapeutic application.

Authors: Adigbli, G

• DOI: 10.5287/ora-mvb22xnao
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: adoptive cell therapy; pre-clinical models; vascularised composite allograft; chemokine; transplant rejection; Treg; regulatory T cell; skin transplantation; VCA; humanised mouse model