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Lotze, M. T.

Publications and source records attributed to Lotze, M. T..

2 recordsLinked to original sources

Computational modeling of cell signaling and mutations in pancreatic cancer

Published research articles are rich sources of data when the knowledge is incorporated into models. Complex biological systems benefit from computational modelings ability to elucidate dynamics, explain data and address hypotheses. Modeling of pancreatic cancer could guide treatment of this devastating disease that has a known mutational profile disrupting signaling pathways but no reliable therapies. The approach described here is to utilize discrete modeling of the major signaling pathways, metabolism and the tumor microenvironment including macrophages. This modeling approach allows for abstraction in order to assemble large networks to capture numerous facets of the biological system under investigation. The Hallmarks of Cancer are represented as the processes of apoptosis, autophagy, cell cycle progression, inflammation, immune response, oxidative phosphorylation and proliferation. The model is initialized with pancreatic cancer receptors and mutations and simulated in time. The model portrays the hallmarks of cancer and suggests combinations of inhibitors as therapies.

systems biology

Adoptive transfer of allogeneic gamma delta T cells promotes HIV replication in a humanized mouse model

Gamma-delta ({gamma}{delta}) T cells recognize antigens in an MHC-independent manner, with demonstrable cytotoxicity against cancer and virally infected cells. Human immunodeficiency virus (HIV) infection severely depletes the V{gamma}9V{delta}2 (V{delta}2) subset of these T cells in most infected individuals, with the exception of elite controllers. The capacity of V{delta}2 cells to kill HIV-infected targets has been demonstrated in vitro, but this has not been verified in vivo. Here, we examined the immunotherapeutic potential of V{delta}2 cells in controlling HIV replication in vivo and provide the first characterization of reconstituted {gamma}{delta} T cell subsets in the peripheral blood and lymphoid tissue in a humanized mouse model. We demonstrate the depletion of V{delta}2 cells and increase in V{delta}1 cells in the blood following HIV infection, similar to that observed in HIV-infected humans. The functionality of human V{delta}2 cells isolated from humanized mice was confirmed via ex vivo expansion in response to zoledronate and IL-2 treatment. The adoptive transfer of activated V{delta}2 cells failed to control HIV infection in vivo but instead exacerbated viremia by serving as early targets for HIV infection. Our findings suggest that V{delta}2 cells play a critical and unappreciated role as early HIV targets of infection to promote viral dissemination.

immunology