Translating the potential of human regulatory B cells in transplantation

Transplantation is the gold standard treatment of choice for many end-stage organ diseases. However, immunosuppressants can result in life-threatening infection and cancer, which are leading causes of death after the 1st year post-transplant. There is little improvement in long-term graft attrition compared to previous eras. The consequences of potent immunosuppression extend to autoimmune diseases: 30% of sufferers remain refractory to immunosuppressive therapy. Novel therapeutic strategies are urgently required to improve outcomes. Regulatory B cells (Breg) can control immune responses in animal models of transplantation and autoimmunity; Breg deficiencies are associated with poor clinical outcomes. I have developed novel methods to expand human Breg (expBreg) with in vivo function, as a precursor to cell therapy. In this new proposal, I will build on this work, using transcriptomics, proteomics, gene editing and humanised mouse models to: i) clarify human expBreg phenotype and ontogeny; ii) identify immunoregulatory signalling pathways and Breg-specific drug targets iii) assess and improve function of kidney transplant recipient-(KTR)-derived Breg of patients with poor clinical outcomes in vivo, as personalised therapy; iv) interrogate stability and specificity of antigen-specific expBreg cell therapy in vivo. My findings will have translational value for autoimmune disorders, bringing Breg cell therapy closer to the clinic.