Janet C Wells
The influence of regulatory T cells and mobilisation regimens on graft versus malignancy, graft versus host disease and relapse in haematopoietic progenitor cell transplantation
Wells, Janet C
Regulatory T cells (Tregs) are key players in controlling immune responses, limiting autoimmune disease and allergies, and attenuating immune responses to tumours and pathogens. Understanding and harnessing the suppressive effects of Tregs in autologous and allogeneic haematopoietic progenitor cell (HPC) transplantation presents a significant challenge due to lack of consensus over optimal markers to uniquely identify Tregs and variation in centre-specific factors including disease mix, conditioning regimens, graft origin and manipulation and prophylaxis and treatment of graft versus host disease (GVHD). This study aimed to determine if CD3+CD4+CD125highCD127lowFoxP3+ Treg quantification, assessed flow cytometrically, in grafts or in the post-transplant peripheral blood of patients who received transplants for malignant disease, could provide a useful predictor for disease relapse in autologous (n=85) and allogeneic patients (n=75) and falling chimerism and/or incidence of GVHD in the latter group. The impact of Treg numbers were quantified in HPC harvests, in transplant grafts and in recipients’ peripheral blood during immune reconstitution. Additionally, a simplified Treg assessment protocol using the marker tumour necrosis factor receptor-2 (TNFR2) with CD3, CD4 and CD25 was assessed.
In autologous donors, significantly higher Tregs relative to CD34 HPCs were noted in harvests mobilised with the more novel regimen, granulocyte-colony stimulating factor (G-CSF) plus Plerixafor than with G-CSF alone or used in combination with cyclophosphamide. In allogeneic harvests Treg numbers following G-CSF mobilisation were significantly lower than in non-mobilised harvests. Lower absolute Treg numbers in donor lymphocyte infusion (DLI) doses were significantly associated with successful outcome in terms of restoration of donor chimerism and resolution of relapse. Cryopreservation of mobilised cells at the time of initial transplant for later use for DLI has thus been incorporated into practice at this Trust as this is expedient in terms of clinical result, convenience and cost. Interestingly although mobilisation regimens influenced Treg levels in harvests, no correlation was apparent between Treg doses transplanted or peripheral blood levels during immune reconstitution post autologous or allogeneic transplantation or with falling chimerism and/or incidence and severity of GVHD in allogeneic patients during the first year post transplant. Extending this follow-up time would be an interesting area of further study as the majority of patients who relapse do so beyond one year.
Wells, J. C. The influence of regulatory T cells and mobilisation regimens on graft versus malignancy, graft versus host disease and relapse in haematopoietic progenitor cell transplantation. (Thesis). University of the West of England
|Keywords||regulatory T cells, mobilisation regimens, graft, malignancy, host disease, relapse, haematopoietic progenitor, cell transplantation|
Thesis with corrections 4.5.15.pdf