The Effect Of Human Peripheral Blood Mononuclear Cells Mobilized By Acute Exercise On Graft-Versus-Host Disease And Graft-Versus-Leukemia In A Humanized Mouse Model



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Hematopoietic cell transplantation and adoptive transfer immunotherapy are critical therapeutic options for patients with hematological malignancies. The lymphocyte composition of the donor graft is known to influence the potentially fatal graft-versus-host disease (GvHD) and the potentially curative graft-versus-tumor (GvT) effects. Increased numbers of NK-cells and γδ T-cells relative to naïve subsets of CD4+ and CD8+ αβ T-cells have been shown to evoke strong GvT effects with minimal GvHD. As single exercise bouts are known to produce these desirable shifts in lymphocyte subset composition, we hypothesized that human immune cells collected from a single bout of exercise will improve engraftment, GvHD, and GvT outcomes when compared to immune cells from rest when xenotransplanted to immunodeficient mice. This dissertation was divided into two specific hypotheses: 1) determine the effect of PBMCs collected during exercise on engraftment and GvHD in a humanized mouse model; and 2) determine the impact of PBMCs collected during exercise on GvT in a humanized mouse model. To test these hypotheses, 12 healthy adults completed a 30-minute bout of exercise that was 15% about their calculated ventilatory threshold. Blood was collected at rest and immediately prior to exercise cessation. Lymphocyte subtypes were determined by flow cytometry prior to transplant. 1 x 107 Human PBMCs and/or 1 x 106 human K562-luc2 leukemia cells were injected intravenously into 8-12 week old NOD.Cg-Prkdcscid Il2rgtm1Wjl Tg(IL15)1Sz/SzJ (NSG-Tg(Hu-IL15) or NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG). Engraftment of human immune cells was tracked weekly, while morbidity scoring and bioluminescence imaging was conducted twice per week for up to 40 days. In support of the hypotheses, tumor-bearing NSGIL-15 mice injected with PBMCs from exercise maintained increased percentages of NK cells and decreased percentages of CD4+ T cells for up to two weeks post-inoculation. Additionally, these mice displayed overall better survival, delayed severe morbidity (GvHD), and an overall reduction in tumor growth compared to mice injected with PBMCs collected from rest. However, improvements in engraftment, morbidity, and survival were not replicated in mouse models of mild or severe GvHD indicating that tumor activation of exercise immune cells was essential for improved outcomes compared to immune cells taken from rest. We conclude that exercising donors prior to transplants can improve disease outcomes for hematopoietic cell transplantations in cancer immunotherapies.



Hematopoietic cell transplantation, Graft-versus-tumor, Graft-versus-host disease