Date of Award

2014

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Microbiology and Immunology

Abstract

Omentum has been harnessed by surgeons for hundreds of years, providing an ideal environment for graft healing and acceptance. However, little is known about the cellular mechanisms that promote the tolergenic environment of the omentum. We examined the cellular composition and role of activated omentum in regards to T-cell immunomodulation. We then tested activated omentum as a cellular therapy in a mouse allogenic lung transplantation model.

Our findings demonstrated activated omentum is mostly comprised of non-hematopoietic cells resembling mesenchymal stem-like cells (MSCs) and myeloid derived suppressor cells (MDSCs). Activated omentum exhibited anti-inflammatory properties through suppression of Th1 and Th17, while promoting tolerance through expansion and survival of Tregs. The mechanism of Th17 inhibition relied on IFNɣ-mediated upregulation of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), leading to generation of nitric oxide (NO) and prostaglandin E2 (PGE2). These mediators inhibited differentiated Th17 cells in vitro, resulting in cell loss, and blockade of cytokine production.

Omentum also caused Th17 cells to become anergic, and unable to flux calcium under TCR-activating conditions. T-cell size and endoplasmic reticulum (ER) were found to be expanded after co-culture suggesting ER stress may be induced by omentum.

Th17 is associated with the development of bronchiolitis obliterans following lung transplantation, a syndrome involving chronic inflammation of airways and development of mucus plugs. We tested the role of omental cells as cellular therapy in our lung transplant model, under the hypothesis these cells could promote a tolergenic response. Transplanted mice treated with omental cells by intraperitoneal administration had reduced airway inflammation. Using a T-cell imaging mouse model, we also observed qualitative decrease in T-cell infiltration within the lung following omental injection. Further studies will be needed to determine administration and dose for optimal therapeutic outcomes.

In conclusion, our lab has demonstrated NO and PGE2 release by activated omentum promoted an anti-inflammatory environment. Furthermore, we are the first lab to test activated omentum as cellular therapy in a rigorous model with preliminary success. Future studies should focus on how omentum can be used as a source of autologous therapy in chronic-inflammatory diseases.

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License.

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