? Beta2 microglobulin knockout mice are deficient in CD8+ T cells and natural killer T cells. Compared to wild type mice, beta2 microglobulin knockout mice exhibit improved survival during sepsis caused by cecal ligation and puncture (CLP). Further depletion of natural killer cells by injection of anti-asialoGM1 confers near complete resistance to CLP-induced mortality. The mechanisms underlying these observations are unknown. However, two potential mechanisms have high probability. Firstly, CD8+ T, natural killer T and natural killer cells can impact innate immune responses by amplifying production of pro-inflammatory cytokines and chemokines. These cell populations can also cause direct cellular injury during inflammation. Therefore, it is hypothesized that CD8+ T, natural killer T and natural killer cells facilitate or directly mediate sepsis-induced mortality by amplifying the pro-inflammatory response and/or causing direct cellular injury. Secondly, beta2 microgiobulin comprises the beta chain of the class I major histocompatibility complex and the non-classical antigen-presenting molecule CD1. Both of these molecules are important for presentation of self and foreign antigens, respectively, but their roles in regulating inflammatory responses during sepsis are unknown. It is further hypothesized that the class I major histocompatibility complex, CD1 and/or unrecognized beta2 microglobulin-associated molecules play a role in modulating the immune response during sepsis. This research project is designed to test these hypotheses. The following specific aims are proposed:
Aim 1 : To determine the specific contributions of CD8+ T, natural killer T and natural killer cells, the class I major histocompatibility complex and CD1 to the pathogenesis of lethal intra-abdominal sepsis. Mortality, bacterial counts, organ injury, cardiovascular function and acid-base balance will be measured following CLP in control mice and mice that are deficient in these cell populations and antigen-presenting molecules.
Specific Aim 2 : To determine the functional roles of CD8+ T, natural killer T and natural killer cells, the class I major histocompatibility complex and CD1 in regulating the pro-inflammatory response during lethal intra-abdominal sepsis. Intra-abdominal and systemic cytokine and chemokine production will be measured following CLP in control mice and mice that are deficient in CD8+ T, natural killer T and natural killer cells, the class I major histocompatibility complex and CD1.
Specific Aim 3 : To determine the role of cytolytic mechanisms in the pathogenesis of lethal intra-abdominal sepsis. We will evaluate expression of perforin, granzymes, Fas and FasL in control mice and mice that are deficient in CD8+ T, natural killer T and natural killer cells after CLP. The functional roles of the perforin/granzyme and Fas-FasL pathways will be determined by assessing survival, cardiovascular function, organ injury and acid-base balance in perforin-deficient and FasL-deficient mice. These studies are designed to define new mechanisms that are important in the pathogenesis of septic shock with the ultimate goal of developing new treatments for this lethal disease process. ? ?
| Guo, Yin; Patil, Naeem K; Luan, Liming et al. (2018) The biology of natural killer cells during sepsis. Immunology 153:190-202 |
| Guo, Yin; Luan, Liming; Patil, Naeem K et al. (2017) Immunobiology of the IL-15/IL-15R? complex as an antitumor and antiviral agent. Cytokine Growth Factor Rev 38:10-21 |
| Patil, Naeem K; Guo, Yin; Luan, Liming et al. (2017) Targeting Immune Cell Checkpoints during Sepsis. Int J Mol Sci 18: |
| Patil, Naeem K; Bohannon, Julia K; Luan, Liming et al. (2017) Flt3 Ligand Treatment Attenuates T Cell Dysfunction and Improves Survival in a Murine Model of Burn Wound Sepsis. Shock 47:40-51 |
| Guo, Yin; Luan, Liming; Patil, Naeem K et al. (2017) IL-15 Enables Septic Shock by Maintaining NK Cell Integrity and Function. J Immunol 198:1320-1333 |
| Patil, Naeem K; Bohannon, Julia K; Sherwood, Edward R (2016) Immunotherapy: A promising approach to reverse sepsis-induced immunosuppression. Pharmacol Res 111:688-702 |
| Patil, Naeem K; Luan, Liming; Bohannon, Julia K et al. (2016) IL-15 Superagonist Expands mCD8+ T, NK and NKT Cells after Burn Injury but Fails to Improve Outcome during Burn Wound Infection. PLoS One 11:e0148452 |
| Hotchkiss, Richard S; Sherwood, Edward R (2015) Immunology. Getting sepsis therapy right. Science 347:1201-2 |
| Guo, Yin; Luan, Liming; Rabacal, Whitney et al. (2015) IL-15 Superagonist-Mediated Immunotoxicity: Role of NK Cells and IFN-?. J Immunol 195:2353-64 |
| Herzig, Daniela S; Luan, Liming; Bohannon, Julia K et al. (2014) The role of CXCL10 in the pathogenesis of experimental septic shock. Crit Care 18:R113 |
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