The immune aspects of physical exercise and photopheresis to ameliorate the adverse effects of stem cell transplantation

Hematopoietic stem cell transplantation (HSCT) is a curative treatment for a number of hematologic disorders. Unfortunately, HSCT can lead to immune complications including graft-versus-host disease (GvHD). Current methods to minimize immune complications are not effective in many patients leading to significant morbidity. Exercise can influence components of the immune system. One clinical trial in allogeneic HSCT patients showed that exercise is safe, has a positive effect on lymphocyte count post-transplant, and can improve patient outcomes. Yet current clinical practices do not reflect this evidence. As part of a randomized controlled trial examining the effects of exercise on quality of life, physical functioning, and immune reconstitution in HSCT patients post-transplant, I performed high-dimensional immunophenotyping and compared the immune composition of patients who exercised (intervention) to those who did not (control). I found that while both groups have similar proportions of major innate and adaptive immune populations, the intervention group had higher proportions of Ki-67⁺ innate lymphoid type 2 cells, elevated frequencies of CD45RA⁺ CD3 and CD8 T cells, and lower proportions of PD-1⁺Tim-3⁺ CD4 T cells. Overall, exercise had anti-immunosenescence effects in HSCT patients. Furthermore, Eomes⁺GATA-3⁺CD56⁺CCR6⁺ innate cells were absent in the exercise group. Meanwhile, another immunomodulatory strategy that may improve patient outcomes is extracorporeal photopheresis (ECP), which aims to induce peripheral tolerance in patients with steroid-refractory or dependent chronic GvHD by depleting alloreactive T cells while sparing regulatory T cells. In a clinical trial assessing the effects of ECP with a novel photosensitizer molecule, TH9402 (CARE trial), I analysed immunophenotyping data and found that this therapy increased the counts of CD57⁺CD45RA- senescent CD4 T cells, HLA-DR⁺ activated CD4 T cells, CD56bright NK cells, and plasmacytoid dendritic cells in most study participants. While the observed immune effects and the extent of the response were heterogeneous among patients, overall, ECP with TH9402 induces a tolerogenic environment in patients with steroid- refractory or dependent chronic GvHD.Medicine, Faculty ofExperimental Medicine, Division ofMedicine, Department ofGraduat