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    Thoracic Duct Lymph Reduces the Production of TNF-alpha IFN-gamma by Pulmonary Leukocytes in vitro
    (2020) House, Sara; Morales, Jessica; Hodge, Lisa; Vo, Russell
    Purpose: Streptococcus pneumoniae, a cause of community acquired pneumonia, accounts for nearly one million hospitalizations in the U.S., annually. The lymphatic pump technique (LPT) is a manipulative medicine technique used by osteopathic physicians to mobilize lymph and treat pneumonia. Our objective was to identify the biological effect of thoracic duct lymph (TDL) mobilized with LPT on the immune response against S. pneumoniae. We hypothesized that lymph mobilized during LPT would suppress the in vitro activity of lung leukocytes in mice infected with S. pneumoniae. Methods: TDL was collected from dogs during 4min of baseline, 4min of LPT, and 10min post-LPT. Mice were intranasally infected with 5x10^5 CFU of S. pneumoniae. Lung leukocytes were isolated from healthy and infected mice (24hr post-infection.) Leukocytes were cultured with media plus 5% saline, 5% baseline TDL, 5% LPT TDL, or 5% post-LPT TDL, and co-cultured with/without LPS. The TNFa and TNFg were measured in supernatants after 24hrs. Results: When cultured with LPS, the addition of baseline LPT, LPT, or post-LPT lymph decreased TNFa and TNFg production by leukocytes from healthy mice. Leukocytes from infected mice did not produce cytokines even when stimulated with LPS, suggesting expended biological activity in vivo. There were no differences in TNFa and TNFg production by leukocytes cultured with baseline LPT, LPT, or post-LPT lymph. Conclusion: TDL reduced inflammatory cytokine production by lung leukocytes. Mobilization of lymph during LPT may release protective factors that limit inflammation and protect the lungs from pulmonary disease.
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    Age-related thymic atrophy impairs development and function of an antigen-specific tTreg cell population
    (2020) Su, Dong-Ming; Oh, Jiyoung; Wang, Weikan; Thomas, Rachel
    Purpose: The atrophied thymus generates an increased ratio of polyclonal thymic T regulatory (tTreg) cells to thymic T conventional (tTcon) cells, and peripheral Treg (pTreg) cells accumulate during aging. So, why are pTregs in the elderly unable to effectively suppress age-related inflammation ("inflammaging")? Methods: We utilized a mock self-antigen (autoimmune pancreatitis) chimeric mouse model, in which irradiated rat insulin promotor-driven (RIP) mOVA mice received mixed OT-II TCR transgenic and wild-type bone marrow. Thus, we can easily visualize the generation and activation of an antigen-specific T cell population. Additionally, our mOVA host mice carry a FoxN1-floxed gene for induction of conditional thymic atrophy, analogous to the aged thymus. Results: The chimeric mice with thymic atrophy exhibited significant decline in central and peripheral OVA-specific (OT-II) Tregs, but not total (pan) Tregs. Further, intrinsic Treg changes in FoxP3 and CD25 expression were observed, likely induced by the atrophied thymic environment. These markers remained decreased even in response to OVA stimulation, suggestive of reduced suppressive capacity. This was confirmed via functional assays showing that OVA-specific Tregs were significantly less able to suppress antigen-specific stimulation of Teffs in vitro. We suspect that thymic atrophy restricts the antigen-specific T cell receptor (TCR) repertoire during tTreg generation, so we are currently conducting TCR repertoire diversity sequencing. Conclusion: Combined with our observed functional defects, if TCR sequencing confirms a reduced tTreg TCR diversity, thymic atrophy has implications for increasing risk of autoimmune predisposition in the elderly.
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    Aged T cell immune system aggravates late-onset experimental autoimmune encephalomyelitis
    (2020) Oh, Jiyoung; Su, Dong-Ming; Wang, Weikan
    Purpose: human multiple sclerosis (MS) mirrored by a mouse model experimental autoimmune encephalomyelitis (EAE) is autoreactive conventional T (Tcon) cell-mediated neuroinflammatory diseases, while regulatory T (Treg) cells can slow the disease. Although MS mostly attacks young adults, its onset is also observed in aged people, termed late-onset MS, which presents a severer progression and more neurological damages, under the aged aberrant T cell immune milieus. However, it is unknown how aged T cells contribute to late-onset MS and what are the underlying mechanism(s). Methods: We use mouse EAE model by immunizing young and aged mice to induce EAE and investigated the disease course and the profiles of Tcon versus Treg cells inside and outside of the central nervous system (CNS). Results: We determined that aged mice had two types of EAE courses, different from the young mice. Type-I: EAE onset in aged group is later than, but rapidly becomes more severe than the young group; Type-II: in some aged mice the severity of EAE symptoms was never stronger than in young mice. However, once the secondary challenge is applied, their symptoms develop faster and are more severe than their young counterparts. Treg cells are accumulated in the peripheral lymphoid organs in aged EAE mice, but not efficiently infiltrating or expanding inside the CNS to restore neuroinflammation. Conclusions: Even though Treg cells are accumulated in the aged periphery, the CNS infiltrated Treg cells are decreased, which are insufficient to protect neurological damages in late-onset EAE.