Characterization and interaction of immunosuppressive cells in burn and sepsis
Immunology
Final Report Abstract
The aim of this work was to characterize immunosuppressive cells and their interaction in trauma such as burn and septic conditions. When writing the application, the major focus was set on a murine model to investigate the quantities and proportional changes of innate and adaptive immune cells and their interaction. Initially we quantified cell numbers but did not find relevant changes in the numbers in murine burn injury. In sepsis we were able to examine relevant mechanisms of T cells controlling neutrophil IL-10 production. It is unclear whether the increase of neutrophilic IL-10 production benefits the host in sepsis resolution as IL-10 mainly but not exclusively moderates immunosuppression. More importantly this led to the assumption that the interaction of CD4 T cells and neutrophils is relevant in the progression of immunosuppression. This interaction seems to be IFNγ dependent. As of that time the spread of Covid-19 in the United States severely affected the experimental progression and halted effective laboratory work for weeks. Thankfully a scholarship extension of 3 months was granted. We shifted the focus from murine work towards a clinical study in which we hypothesized that for the first time we can reliably predict the outcome of trauma and sepsis patients in intensive care using functional immunomonitoring. The University of Florida (Prof. L. Moldawer), Washington University (Prof. R. Hotchkiss) and our institution initiated and started the study. Despite this being a significant change in the experimental plan it was more importantly an opportunity to assess the cause of immunosuppression in human ICU patients. We established a functional assessment of stimulated myeloid TNFα- and lymphoid IFNγ-production using the enzyme-linked immune absorbent spot (Elispot) technique. Briefly we found that both myeloid and lymphoid TNFα and IFNγ production is reduced in septic and critically ill non-septic patients. Moreover, we were able to show that it is possible to predict outcome at day 4 and 7 into the disease progression in the intensive care unit. The preliminary results were presented at the 44th Conference on Shock 2021. The clinical study is ongoing, and the results expected to be published within the next two years. My personal contribution beside processing the samples and the interpretation of the data was the development of the optimal technique and the collaboration with the company manufacturing the tests, Cellular Technology Limited (CTL), to improve the software analysis with our data. Successful side projects were a cooperation with the University of California, Davis (Prof. B. Hammock) in which we investigated how oxylipins contribute to innate immune dysfunction in a murine burn trauma model. The work led to a published manuscript and a publication submitted to PNAS (IF 2020: 11,2) which is currently under review. A cooperation for a clinical study at my new institution the University of Ulm is in the planning process. At the University of Cincinnati we started a clinical trial assessing myeloid and lymphoid functionality using Elispot to predict wound healing and outcome of diabetic patients with an infection of the feet. Preliminary results have been published on the 81st Scientific Session of the American Diabetes Association in 2021. I am currently in the process of establishing a clinical trial at the University of Ulm to extend the study to an international, multi-center study.
Publications
- Intraperitoneal Neutrophil IL-10 production is promoted by interferon γ in a murine model of sepsis model in the acute phase of sepsis. Biochemical and Biophysical Research Communications, Vol. 530. 2020, Issue 1, pp. 278-284.
Bergmann C.B., Salyer C.E., Beckmann N., Caldwell C.C.
(See online at https://doi.org/10.1016/j.bbrc.2020.07.089) - Lymphocyte Immunosuppression and Dysfunction Contributing to Persistent Inflammation, Immunosuppression, and Catabolism Syndrome (PICS). Shock, Vol. 55. 2021, Issue 6, pp. 723-741.
Bergmann C.B., Beckmann N., Salyer C.E., Crisologo P.A., Nomellini V., Caldwell C.C.
(See online at https://dx.doi.org/10.1097/SHK.0000000000001675) - Potential Targets to Mitigate Trauma- or Sepsis-Induced Immune Suppression.
Front Immunol. , Vol. 12. 2021: 622601.
Bergmann C.B., Beckmann N., Salyer C.E., Hanschen M., Crisologo P.A., Caldwell C.C.
(See online at https://doi.org/10.3389/fimmu.2021.622601) - TPPU treatment of burned mice dampens inflammation and generation of bioactive DHET which impairs neutrophil function. Scientific Reports, Vol. 11. 2021, Article number: 16555.
Bergmann C.B., Hammock B.D., Wan D., Gogolla F., Goetzman H., Caldwell C.C., Supp D.M.
(See online at https://doi.org/10.1038/s41598-021-96014-2) - sEH-derived metabolites of linoleic acid drive pathologic inflammation while impairing key innate immune cell function in burn injury.
PNAS, Vol. 119. 2022, Issue 13, e2120691119.
Bergmann C.B., McReynolds C.B., Wan D., Singh N., Goetzman H., Caldwell CC., Supp D.M., Hammock B.D.
(See online at https://doi.org/10.1073/pnas.2120691119)
