Severity of Sepsis Determines the Degree of Impairment Observed in Circulatory and Tissue-Resident Memory CD8 T Cell Populations.

Sepsis reduces the number and function of memory CD8 T cells within the host, contributing to the long-lasting state of immunoparalysis. Interestingly, the relative susceptibility of memory CD8 T cell subsets to quantitative/qualitative changes differ after cecal ligation and puncture (CLP)-induced sepsis. Compared with circulatory memory CD8 T cells (T), moderate sepsis (0-10% mortality) does not result in numerical decline of CD8 tissue-resident memory T cells (T), which retain their "sensing and alarm" IFN-γ-mediated effector function.

Ectopic Tcf1 expression instills a stem-like program in exhausted CD8 T cells to enhance viral and tumor immunity.

Exhausted CD8 T (Tex) cells are dysfunctional due to persistent antigen exposure in chronic viral infection and tumor contexts. A stem cell-like Tex (Tex-stem) subset can self-renew and differentiate into terminally exhausted (Tex-term) cells. Here, we show that ectopic Tcf1 expression potently promoted the generation of Tex-stem cells in both a chronic viral infection and preclinical tumor models.

Cutting Edge: Antitumor Immunity by Pathogen-Specific CD8 T Cells in the Absence of Cognate Antigen Recognition.

Cancer prognosis often correlates with the number of tumor-infiltrating CD8 T cells, but many of these cells recognize pathogens that commonly infect humans. The contribution of pathogen-specific "bystander" CD8 T cells to antitumor immunity remains largely unknown. Inflammatory cytokines are sufficient for memory CD8 T cell activation and gain of effector functions, indicating tumor-derived inflammation could facilitate pathogen-specific CD8 T cells to participate in tumor control.

Microbial Exposure Enhances Immunity to Pathogens Recognized by TLR2 but Increases Susceptibility to Cytokine Storm through TLR4 Sensitization.

Microbial exposures can define an individual's basal immune state. Cohousing specific pathogen-free (SPF) mice with pet store mice, which harbor numerous infectious microbes, results in global changes to the immune system, including increased circulating phagocytes and elevated inflammatory cytokines. How these differences in the basal immune state influence the acute response to systemic infection is unclear.

Sepsis-Induced State of Immunoparalysis Is Defined by Diminished CD8 T Cell-Mediated Antitumor Immunity.

Patients who survive sepsis experience long-term immunoparalysis characterized by numerical and/or functional lesions in innate and adaptive immunity that increase the host's susceptibility to secondary complications. The extent to which tumor development/growth is affected in sepsis survivors remains unknown. In this study, we show cecal ligation and puncture (CLP) surgery renders mice permissive to increased B16 melanoma growth weeks/months after sepsis induction.

Cutting Edge: Polymicrobial Sepsis Has the Capacity to Reinvigorate Tumor-Infiltrating CD8 T Cells and Prolong Host Survival.

Malignancy increases sepsis incidence 10-fold and elevates sepsis-associated mortality. Advances in treatment have improved survival of cancer patients shortly after sepsis, but there is a paucity of information on how sepsis impacts cancer growth, development, and prognosis. To test this, cecal ligation and puncture surgery was performed on B16 melanoma-bearing mice to show that sepsis has detrimental effects in hosts with advanced tumors, leading to increased mortality.

Polymicrobial Sepsis Chronic Immunoparalysis Is Defined by Diminished Ag-Specific T Cell-Dependent B Cell Responses.

Immunosuppression is one hallmark of sepsis, decreasing the host response to the primary septic pathogens and/or secondary nosocomial infections. CD4 T cells and B cells are among the array of immune cells that experience reductions in number and function during sepsis. "Help" from follicular helper (Tfh) CD4 T cells to B cells is needed for productive and protective humoral immunity, but there is a paucity of data defining the effect of sepsis on a primary CD4 T cell-dependent B cell response.

Revealing the Complexity in CD8 T Cell Responses to Infection in Inbred C57B/6 versus Outbred Swiss Mice.

Recent work has suggested that current mouse models may underrepresent the complexity of human immune responses. While most mouse immunology studies utilize inbred mouse strains, it is unclear if conclusions drawn from inbred mice can be extended to all mouse strains or generalized to humans. We recently described a "surrogate activation marker" approach that could be used to track polyclonal CD8 T cell responses in inbred and outbred mice and noted substantial discord in the magnitude and kinetics of CD8 T cell responses in individual outbred mice following infection.

Polymicrobial sepsis impairs bystander recruitment of effector cells to infected skin despite optimal sensing and alarming function of skin resident memory CD8 T cells.

Sepsis is a systemic infection that enhances host vulnerability to secondary infections normally controlled by T cells. Using CLP sepsis model, we observed that sepsis induces apoptosis of circulating memory CD8 T-cells (TCIRCM) and diminishes their effector functions, leading to impaired CD8 T-cell mediated protection to systemic pathogen re-infection. In the context of localized re-infections, tissue resident memory CD8 T-cells (TRM) provide robust protection in a variety of infectious models.

Polymicrobial Sepsis Diminishes Dendritic Cell Numbers and Function Directly Contributing to Impaired Primary CD8 T Cell Responses In Vivo.

Patients surviving acute stages of sepsis often display impaired adaptive-immune responses. Using the cecal ligation and puncture model, we demonstrated that sepsis leads to substantial and long-lasting changes in the naive CD8 T cell repertoire, affecting the capacity of the host to respond to new infections. However, the identity of CD8 T cell-extrinsic factor(s) and mechanism(s) that contribute to impaired CD8 T cell responses after sepsis is unknown.

Clinical and Experimental Sepsis Impairs CD8 T-Cell-Mediated Immunity.

Septic patients experience chronic immunosuppression resulting in enhanced susceptibility to infections normally controlled by T cells. Clinical research on septic patients has shown increased apoptosis and reduced total numbers of CD4 and CD8 T cells, suggesting contributing mechanism driving immunosuppression. Experimental models of sepsis, including cecal ligation and puncture, reverse translated this clinical observation to facilitate hypothesis-driven research and allow the use of an array of experimental tools to probe the impact of sepsis on T-cell immunity.

Timely blockade of ICAM-1.LFA-1 interaction prevents disease onset in a mouse model of emphysema.

Aim: It is becoming apparent that emphysema is partly driven by self-reactive T cells inducing inflammatory damage. Thus, T cells become targets for therapy similar to other autoimmune diseases. Costimulatory blockade therapy targets disease-specific T cells, rendering them ineffective by blocking a necessary costimulatory event on the T-cell surface.

First-pass or single-pass radionuclide angiography evaluation of left ventricular ejection fraction using a microcomputer system.

Left ventricular ejection fractions of 31 patients determined from first-pass or single-pass radionuclide angiography from the anterior position using a microcomputer system and floppy disc were compared to angiographic catheterization data obtained from the right anterior oblique position. This study demonstrated a good correlation with r = 0.91.

Comparison of left ventricular ejection fraction by EKG-gated radionuclide techniques and contrast angiography using a microcomputer system.

The left ventricular ejection fractions of 53 patients were determined from multi-image cardiac blood pool scintigrams in the left anterior oblique position utilizing a microcomputer and floppy disc. These data were compared to ejection fractions obtained at cardiac catheterization in the right anterior oblique position. The ejection fraction obtained by radionuclide technique was comparable to that obtained by contrast angiography in the 53 patients with an r = 0.

Comparison of noninvasive with hemodynamic data in patients with pulmonary hypertension due to chronic obstructive pulmonary disease.

Twenty-one patients with chronic obstructive pulmonary disease were studied with right heart catheterization. The mean pulmonary artery pressure (PAP) was compared with several noninvasive tests. The pulmonary lobar diameter/thoracic ratio correlated with the PAP, r = 0.

Effects of isosorbide dinitrate on pulmonary hypertension in chronic obstructive pulmonary disease.

Eighteen patients with chronic obstructive pulmonary disease with pulmonary hypertension were studied to assess the hemodynamic response to acute oxygen administration and to oral isosorbide dinitrate (ISDN). All 18 patients had baseline hemodynamic measurements and hemodynamic measurements during low-flow nasal oxygen. Following a second baseline measurement, patients received either oral ISDN (11 patients) or placebo (7 patients) in a randomized, double-blind protocol.

Effect of trimazosin on hemodynamics in chronic heart failure.

The effect of the oral vasodilator trimazosin on hemodynamics in 16 patients with chronic left ventricular failure was compared with placebo in a double-blind, randomized study. Eight patients received trimazosin 100 to 300 mg, and 8 received placebo. Over the 6-hr period after medication trimazosin caused no significant change in heart rate, stroke work index, or pulmonary vascular resistance, but there were significant reductions in mean arterial pressure (p less than 0.

Efficacy of trimazosin and prazosin therapy on cardiac and exercise performance in outpatients with chronic congestive heart failure.

The effect of trimazosin versus placebo therapy in 16 patients and of prazosin versus placebo therapy in six patients on treadmill exercise performance was evaluated in two double-blind, randomized studies in patients with chronic left ventricular failure despite therapy with digitalis and diuretics. The administration of trimazosin and prazosin was effective in lowering resting systolic and diastolic blood pressures and resting heart rate times systolic blood pressure, and the administration of trimazosin was effective in decreasing exercise diastolic blood pressure. Trimazosin and prazosin therapy was also effective in diminishing clinical symptoms, in lessening roentgenographic evidence of pulmonary venous congestion and in improving exercise duration until marked dyspnea.

Lidocaine-induced cardiac rate changes in atrial fibrillation and atrial flutter.

To assess atrial and ventricular rate changes after lidocaine injection, 18 atrial flutter patients and 35 atrial fibrillation patients were given intravenous lidocaine, mean dose 100 mg. Continuous electrocardiographic recording for 5 minutes before and at least 10 minutes after lidocaine injection was used to determine rate changes. The atrial flutter rate decreased after lidocaine in 17 of 18 patients (94 per cent), mean maximal decrease 27 beats/minute.

Pseudo subaortic stenosis--a catheter-induced artifact.

Three cases are reported of valvular aortic stenosis in which artifactual subvalvular chambers were recorded on pressure tracings. The pressure tracings were obtained during withdrawal of multiholed catheters from the left ventricle to the aortic root. Several recent reports have described the coexistence of valvular and subvalvular aortic stenosis.

Effect of the vasodilator trimazosin versus placebo on exercise performance in chronic left ventricular failure.

The effect of the vasodilator trimazosin versus placebo on exercise duration until marked dyspnea was evaluated in a double blind randomized study in 16 patients with chronic left ventricular failure despite digitalis and diuretic therapy. Trimazosin caused a reduction in resting systolic and diastolic blood pressures and in resting product of systolic blood pressure times heart rate. The improvement in exercise duration from the average of values during the baseline and single blind placebo periods was greater after 3 and 6 weeks of trimazosin therapy (300 and 450 mg daily) after 3 and 6 weeks of double blind placebo therapy (P is less than 0.

Hemodynamics and antianginal effects of high dose oral isosorbide dinitrate after chronic use.

In a randomized, double-blind, crossover study, 19 patients with angina were exercised 2 min after 0.4 mg sublingual nitroglycerin and after sublingual placebo and before and 1, 3, and 5 hours after oral isosorbide dinitrate (ISDN) and oral placebo. After initial testing, patients took the dose of ISDN they had had during the study (mean dose 29 mg) for a mean period of 5.

Sustained hemodynamic and antianginal effect of high dose oral isosorbide dinitrate.

Twenty-one patients with documented coronary atherosclerotic heart disease were studied to determine the effect of high dose oral isosorbide dinitrate (ISDN) on heart rate, blood pressure, and exercise time until angina pectoris. Patients were tested in two phases, initially with 0.4 mg of sublingual nitroglycerin and with sublingual placebo, and then with oral ISDN, mean dose 29 mg, and oral placebo.

Propranolol and lidocaine. Clinical use as antiarrhythmic agents.

Using propranolol or lidocaine as an antiarrhythmic agent takes keen clinical judgment if optimal efficacy is to be obtained or minimal risk. Serious adverse effects of propranolol are cardiac, while those of lidocaine are usually dose-related and most often involve the central nervous system.