Effect of Exogenously Applied Endothelial Cells in Thymic Regeneration After Hematopoietic Stem Cell Transplantation
Final Report Abstract
Allo-HCT is a curative-intent therapy of numerous hematological malignancies. Despite advances in the field, the broader implementation of allo-HCT is limited by high rates of transplant-related complications, with 3-year overall mortality approaching 50% (41). The goal of my postdoctoral projects was to study immune reconstitution after allo-HCT, factors influencing the reconstitution of specific immune cell subsets and strategies to improve immune reconstitution and diminish the risk of relapse. In Aim 1, I was able to demonstrate a novel link between early post-transplantation gut microbiome and its metabolic activity and MAIT and Vd2 cell populations. I was also able to link their early reconstitution to a positive effect on allo-HCT outcomes, especially the GVHD development. Although the mechanism of protection remains not completely clear, I speculate that the upregulation of the proinflammatory and cytotoxic genes in microbiota-responsive populations could reflect a role for these populations in controlling pathogenenic bateria or cell populations. In Aim 2, I was able to demonstrate that genetic modification of precursor T cells with orthogonal interleukin 7 receptor and their consecutive stimulation with the corresponding orthogonal cytokine in vivo leads to improved thymic reconstitution early post-transplantation and higher CD4 and CD8 proportions in the lymph nodes compared to the precursor T cells without stimulation. I also showed that precursor T cells can be transduced with a CAR construct and migrate to the thymus when the CAR is not signaling. Further experiments are needed to develop genetically modified precursor T cells into a more potent booster of post-transplantation T cell immunity and mature, donor unrestricted CAR T cells fighting possible relapse after allo-HCT. I feel that my research has helped to gain some additional understanding of immune reconstitution and function and the factors influencing these processed, such as gut microbiome. I have also had a deeper insight in developing new cellular therapies to improve immune reconstitution and anti-tumor responses. I have extended my postdoctoral time in the van den Brink lab and am currently still working on the Aim 2 of the proposal.
Publications
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An Unconventional View of T Cell Reconstitution After Allogeneic Hematopoietic Cell Transplantation. Front. Oncol., 2021 Feb 18;10:608923
Andrlová H, van den Brink MRM, Markey KA
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Dynamic structural cell responses in the thymus to acute injury, regeneration, and age
Lorenz Jahn, Anastasia I. Kousa, Lisa Sikkema, Angel E. Flores, Kimon V. Argyropoulos, Jennifer Tsai, Amina Lazrak, Katherine Nichols, Nichole Lee, Florent Malard, Hana Andrlova, Antonio L.C. Gomes, Enrico Velardi, Salma Youssef, Marina B. da Silva, Melissa Docampo, Roshan Sharma, Linus Mazoutis, Manu Setty, Dana Pe’er, Nancy R. Manley, Jarrod A. Dudakov, Marcel R.M. van den Brink
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Early intestinal microbial features are associated with CD4 T cell recovery after allogeneic hematopoietic transplant. Blood. 2022 Jan 21:blood.2021014255
Miltiadous O, Waters NR, Andrlova H, Dai A, Nguyen CL, Burgos da Silva M, Lindner S, Slingerland J, Giardina P, Clurman A, Armijo GK, Gomes AL, Lakkaraja M, Maslak PG, Scordo M, Shouval R, Staffas A, O'Reilly RJ, Taur Y, Prockop S, Boelens JJ, Giralt S, Perales MA, Devlin SM, Peled JU, Markey KA, van den Brink MRM
