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Multiple sclerosis is a neurodegenerative disease characterized by episodes of autoimmune attack of oligodendrocytes leading to demyelination and progressive functional deficits. Because many patients exhibit functional recovery in between demyelinating episodes, understanding mechanisms responsible for repair of damaged myelin is critical for developing therapies that promote remyelination and prevent disease progression. The chemokine CXCL12 is a developmental molecule known to orchestrate the migration, proliferation, and differentiation of neuronal precursor cells within the developing CNS. Although studies suggest a role for CXCL12 in oligodendroglia ontogeny in vitro, no studies have investigated the role of CXCL12 in remyelination in vivo in the adult CNS. Using an experimental murine model of demyelination mediated by the copper chelator cuprizone, we evaluated the expression of CXCL12 and its receptor, CXCR4, within the demyelinating and remyelinating corpus callosum (CC). CXCL12 was significantly up-regulated within activated astrocytes and microglia in the CC during demyelination, as were numbers of CXCR4+NG2+ oligodendrocyte precursor cells (OPCs). Loss of CXCR4 signaling via either pharmacological blockade or in vivo RNA silencing led to decreased OPCs maturation and failure to remyelinate. These data indicate that CXCR4 activation, by promoting the differentiation of OPCs into oligodendrocytes, is critical for remyelination of the injured adult CNS.

Dogs serve as a promising aging model due to their genetic diversity, condensed lifespan, and shared living environment with humans. Alterations in the immune and metabolic parameters are hallmarks of aging in humans, but few studies have investigated these changes in dogs. We investigated the association of whole blood parameters with aging in a cross-sectional field study with a population of 451 companion dogs. Additionally, we measured total lymphocytes, total T-cells, CD4 T-cells, CD8 T-cells, B-cells, CBC, insulin and adiponectin in a cross-sectional study of 74 laboratory research beagles. In companion dogs, we report total lymphocytes and RBCs decrease significantly with age while platelets increase significantly. In lab beagles, total lymphocytes, T-cells, CD4 T-cells, CD8 T-cells, and B cells are significantly lower in Aged and Geriatric beagles. Furthermore, the CD4/CD8 ratio is significantly lower in Geriatric beagles. We also found that Geriatric beagles experience hyperinsulinemia, while plasma adiponectin is significantly lower in both Aged and Geriatric beagles. These results align with the age-related immune and metabolic alterations seen in humans and provide additional evidence that dogs serve as a relevant translational model of aging.

Declining metabolic function with aging is a conserved phenotype across many species. While aging-associated changes in metabolic status have been investigated rigorously in humans, less is known about metabolic aging in dogs. In this cross-sectional study, we aimed to examine changes in metabolic health with age, and any associations with frailty and quality of life, in a diverse population of companion dogs. This cross-sectional study enrolled 451 mature, adult companion dogs. Serum adiponectin, ALP, ALT, AST, cholesterol, insulin, IGF-1 and glucose levels were quantified. Additionally, plasma FFA, SFA, PA, OA and LA were quantified in a 61 dog subpopulation. All analytes were significantly associated with age, with the exception of AST. Elevated ALP, ALT, cholesterol, insulin, FFA, PA and OA were correlated with increased frailty scores, while higher levels of glucose and adiponectin were correlated with reduced frailty scores. The strength of these associations increased with age. Higher ALP, ALT and insulin were associated with lower HRQL scores after adjusting for covariates. Our findings establish novel associations between deleterious aging-associated metabolic changes and validated measures of clinical well-being in companion dogs. Future research should investigate the causality of these associations to inform therapeutic strategies targeting age-associated changes to frailty and quality of life.

Multiple sclerosis (MS) is an inflammatory disease of the CNS that is characterized by BBB dysfunction and has a much higher incidence in females. Compared with other strains of mice, EAE in the SJL mouse strain models multiple features of MS, including an enhanced sensitivity of female mice to disease; however, the molecular mechanisms that underlie the sex- and strain-dependent differences in disease susceptibility have not been described. We identified sphingosine-1-phosphate receptor 2 (S1PR2) as a sex- and strain-specific, disease-modifying molecule that regulates BBB permeability by destabilizing adherens junctions. S1PR2 expression was increased in disease-susceptible regions of the CNS of both female SJL EAE mice and female patients with MS compared with their male counterparts. Pharmacological blockade or lack of S1PR2 signaling decreased EAE disease severity as the result of enhanced endothelial barrier function. Enhanced S1PR2 signaling in an in vitro BBB model altered adherens junction formation via activation of Rho/ROCK, CDC42, and caveolin endocytosis-dependent pathways, resulting in loss of apicobasal polarity and relocation of abluminal CXCL12 to vessel lumina. Furthermore, S1PR2-dependent BBB disruption and CXCL12 relocation were observed in vivo. These results identify a link between S1PR2 signaling and BBB polarity and implicate S1PR2 in sex-specific patterns of disease during CNS autoimmunity.

Background This prospective, non-inferiority study was designed to evaluate the serologic response to booster vaccination in dogs previously vaccinated according to standard of care practice and treated for 56 days with up to 3X the recommended label dose of ilunocitinib. Vaccination occurred 28 days post-treatment initiation and continued through day 56. Measured study parameters included: vaccine-induced serum antibody titers at 15- and 28-day post-vaccination, along with hematological and clinical chemistry parameters. Results Serum antibody titer levels were not significantly different between the control and ilunocitinib treated groups (1X and 3X), and both met the non-inferiority criteria versus the control group after 56 days of treatment (SD 56). All dogs administered ilunocitinib had titers at or above threshold for rabies, CAV-2, and CPV at 15- and 28-day post-vaccination timepoints (SD 43 and SD 56, respectively). The percentage of dogs with titers at or above threshold on SD 43 for CDV were 96, 100, and 95% in the control, 1X and 3X groups, respectively. By SD 56, the percentage of animals with titers above threshold for CDV were similar to pre-vaccination levels in all groups. Conclusion This study demonstrated treatment with ilunocitinib at 1X or 3X the therapeutic dose for 56 days did not significantly attenuate the serologic response to CAV-2, CPV, CDV or rabies booster vaccinations compared to untreated control animals. All animals remained clinically healthy during the study, with only mild gastrointestinal or skin abnormalities typical of laboratory dogs or JAK inhibitor therapy.

Background This study was designed to test the effect of a novel JAK inhibitor, ilunocitinib, on the response to modified live and inactivated vaccines when given at three times the label dose to healthy, vaccine-naive, seronegative, juvenile (10-month-old) purpose-bred research dogs. During the study, an outbreak of infectious diseases occurred including coccidiosis and a confirmed case of infectious canine hepatitis. Although confounded by disease, the data provides information to researchers and clinicians on a new member of this important class of therapeutics. Results Opportunistic infection by Cystoisospora canis was confirmed during the study and associated with mild to severe gastrointestinal disease. Morbidity was higher in the treated group compared to placebo controls and two treated dogs were humanely euthanized due to deterioration of overall health status. Decreased body condition and impaired CD4 T helper cell counts correlated with disease severity. After study completion, Canine Adenovirus Type-1 was identified via PCR in one dog. Despite an outbreak of concurrent disease, all dogs successfully achieved threshold titers to multivalent modified live vaccination administered on day 28. On day 88, responses to modified live booster and inactivated primary rabies vaccinations were decreased where 2/6 treated dogs versus all controls successfully responded to rabies vaccination. Lack of response was correlated to individuals with the most prominent clinical disease and lowest CD4 T helper cell counts. At the end of the treatment phase (day 88), all dogs recovered from disease and most demonstrated improved rabies titer levels by day 116. Conclusion Considering the mechanism of JAK inhibitors, it is not surprising dogs receiving three times the expected dose of drug had higher incidence of parasitic and viral disease compared to controls. In the face of these confounding infectious diseases, it was also not surprising that treated dogs had lower measures of health status correlating directly to both disease severity and inactivated vaccine response. Although confounding disease prevents a definitive conclusion regarding the original intent of the study, it was interesting that there was sufficient threshold response relating to the initial modified live vaccination across both control and Jak inhibitor treated groups administered on day 28, however this was not the primary endpoint of the study.

The migration of lymphocytes into the CNS during viral encephalitis is hindered by the blood-brain barrier (BBB) such that most infiltrating cells remain localized to perivascular spaces. This sequestration of leukocytes away from the parenchyma is believed to protect the CNS from immunopathologic injury. Infections of the CNS with highly cytopathic neurotropic viruses, such as West Nile virus (WNV), however, require the parenchymal penetration of T lymphocytes for virus clearance and survival, suggesting that perivascular localization might hinder antiviral immune responses during WNV encephalitis. Using human and murine brain specimens from individuals with WNV encephalitis, we evaluated the expression of CXCL12 and its receptor, CXCR4, at the BBB and tested the hypothesis that inhibition of CXCR4 would promote T lymphocyte entry into the CNS parenchyma and increase viral clearance. Antagonism of CXCR4 significantly improved survival from lethal infection through enhanced intraparenchymal migration of WNV-specific CD8⁺ T cells within the brain, leading to reduced viral loads and, surprisingly, decreased immunopathology at this site. The benefits of enhanced CD8⁺ T cell infiltration suggest that pharmacologic targeting of CXCR4 may have therapeutic utility for the treatment of acute viral infections of the CNS.

Background Bovine respiratory disease (BRD) is a major problem affecting beef cattle after arrival to feedlots. Alternatives to antibiotics are needed for prevention. Hypothesis Stimulation of pulmonary innate immune responses at the time of arrival to a feedlot reduces the occurrence and severity of BRD. Animals Sixty beef steers at high risk of BRD. Methods Randomized, double‐blinded, placebo‐controlled study. Calves received saline or a lysate of Staphylococcus aureus and Escherichia coli by aerosol, at 16 hours after feedlot arrival. Calves were monitored for 28 days for disease outcomes and levels of Mycoplasma bovis and Mannheimia haemolytica in nasal swabs. Results Death from M bovis pneumonia was significantly greater in lysate‐treated animals (6/29, 24%) compared to controls (1/29, 3%; odds ratio = 10.2; 95% confidence interval [CI] = 1.1‐96.0; P = .04). By 28 days after arrival, 29/29 lysate‐treated calves had ultrasonographic pulmonary consolidation compared to 24/29 control calves (P = .05). Lysate‐treated calves had lower weight gain compared to control calves (−8.8 kg, 95% CI = −17.1 to −0.5; P = .04), and higher body temperatures on days 4, 7, and 21 (0.19°C; 95% CI = 0.01‐0.37; P = .04). Nasal M bovis numbers increased over time and were higher in lysate‐treated calves (0.76 log CFU, 95% CI = 0.3‐1.2; P = .001). Conclusions and Clinical Importance Aerosol administration of a bacterial lysate exacerbated BRD in healthy high‐risk beef calves, suggesting that respiratory tract inflammation adversely affects how calves respond to subsequent natural infection with M bovis and other respiratory pathogens.

Background Constitutive and inducible defenses protect the respiratory tract from bacterial infection. The objective of this study was to characterize the response to an aerosolized lysate of killed bacteria, as a basis for studying the regulation and in vivo effects of these inducible innate immune responses. Results Bacterial lysate consisting of heat-killed and sonicated Staphylococcus aureus and Escherichia coli was aerosolized to 6 calves and systemic and pulmonary innate immune and inflammatory responses were measured in the first 24 h relative to baseline. Evaluated parameters included clinical parameters (body temperature and heart and respiratory rates), blood acute phase proteins and leukocyte counts, and leukocytes and proteins in bronchoalveolar lavage fluid. Mild clinical signs with increased heart rates and rectal temperatures developed following administration of the lysate, with resolution by 24 h. Serum haptoglobin and plasma fibrinogen concentrations were elevated at 24 h relative to baseline. Bronchoalveolar lavage fluid (BALF) had increased cellularity and increased proportion of neutrophils, as well as higher concentrations of interleukin (IL)-8, IL-10 and total protein at 24 h relative to baseline. Mass spectrometry identified 965 unique proteins in BALF: 19 proteins were increased and 26 proteins were decreased relative to baseline. The upregulated proteins included those involved in innate immunity including activation of complement, neutrophils and platelets. At postmortem examination, calves receiving higher doses of lysate had areas of lobular consolidation and interlobular edema. Histologically, neutrophils were present within bronchioles and to a lesser extent within alveoli. Calves receiving highest doses of lysate had patchy areas of neutrophils, hemorrhage and hyaline membranes within alveoli. Conclusions Aerosolization of bacterial lysate stimulated an innate immune response in lungs and airways, with alveolar damage observed at higher doses. Such a stimulus could be of value for investigating the effects of inducible innate immune responses on occurrence of disease, or for evaluating how stress, drugs or genetics affect these dynamic responses of the respiratory tract.

Autoimmune diseases of the central nervous system (CNS) involve the migration of abnormal numbers of self-directed leukocytes across the blood–brain barrier that normally separates the CNS from the immune system. The cardinal lesion associated with neuroinflammatory diseases is the perivascular infiltrate, which comprises leukocytes that have traversed the endothelium and have congregated in a subendothelial space between the endothelial-cell basement membrane and the glial limitans. The exit of mononuclear cells from this space can be beneficial, as when virus-specific lymphocytes enter the CNS for pathogen clearance, or might induce CNS damage, such as in the autoimmune disease multiple sclerosis when myelin-specific lymphocytes invade and induce demyelinating lesions. The molecular mechanisms involved in the movement of lymphocytes through these compartments involve multiple signalling pathways between these cells and the microvasculature. In this review, we discuss adhesion, costimulatory, cytokine, chemokine and signalling molecules involved in the dialogue between lymphocytes and endothelial cells that leads to inflammatory infiltrates within the CNS, and the targeting of these molecules as therapies for the treatment of multiple sclerosis.