Impact of T Cells on Age-related Vascular Dysfunction: A Translational Approach

Cardiovascular Diseases Clinical Trial

Official title:

Impact of T Cells on Age-related Vascular Dysfunction: A Translational Approach

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT04344873
• Other study ID #: IRB_00118392
• Secondary ID: R01AG060395
• Status: Not yet recruiting
• Phase: Early Phase 1
• Start date: August 1, 2024
• Est. completion date: August 1, 2025

Study information

• Verified date: May 2024
• Source: University of Utah
• Contact: Anthony Donato
• Phone: 801-584-2522
• Email: tony.donato[@]hsc.utah.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in the United States and other industrialized societies, and advanced age is the major risk factor for development of CVD. Advancing age appears to exert its pathological influence primarily via adverse functional and structural effects on arteries. Aging is associated with increased stiffness (reduced compliance) of large elastic arteries and impaired arterial endothelial function that is characterized by reductions in nitric oxide (NO)- mediated endothelium-dependent dilation (EDD). While several changes to arteries may contribute to age-associated increases in CVD risk; the development of endothelial dysfunction and stiffening of the large elastic arteries are among the most important contributors. Both are predictors of CV events and clinical CVD with increasing age. Although the importance of endothelial dysfunction and arterial stiffening with age are well established, the initiating events of these deleterious changes are elusive.

Description:

Advanced age is the primary and most predictive risk factor for CVD. The investigators have demonstrated that there is a pronounced age-associated increase in T cell infiltration into the perivascular space around large elastic arteries and small resistance arteries. The objective of this study is to determine if and how T cells contribute to age-related arterial inflammation and dysfunction. Although there is evidence from rodent studies that T cells play a critical role in arterial dysfunction, it is unknown whether this occurs in humans. Abatacept, a T cell co-stimulation inhibitor, is FDA approved for treatment of rheumatoid arthritis. Importantly, Abatacept decreases the inflammatory phenotype of circulating T cells. Abatacept will be used in older adults to be the first to determine if T cell inflammation contributes to arterial dysfunction in older adults. The investigators hypothesize that older adults treated with Abatacept will exhibit greater flow-mediated dilation, decreased pulse wave velocity, decreased or unchanged blood pressure, decreased inflammatory and oxidative stress markers in endothelial cells, decreased plasma free radicals, decreased proportion of memory T cells, and experience a shift away from a pro-inflammatory T cell phenotype compared to placebo. These results will be interpreted to mean that T cells play a role in mediating age-related arterial dysfunction in humans.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 20
• Est. completion date: August 1, 2025
• Est. primary completion date: August 1, 2025
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 55 Years to 75 Years

Eligibility

Inclusion Criteria:

• Older adults (55-75 years old).
• Women will be at least two years postmenopausal, not using hormone therapy and have a follicle stimulating hormone (FSH) concentration of >30 IU/L.

Exclusion Criteria:

• Autoimmune disorders,
• Hypertension (blood pressure >140/90mmHg),
• Body mass index of >30 kg/m2,
• Clinical CVD,
• Diabetes
• Current tobacco use,
• Regular aerobic exercise (>30 mins per day, > 2 days per week for the at least the last 2 years),
• Current or recurring infections within 12 weeks of the baseline visit,
• A positive tuberculosis (TB) test or subjects at risk of TB,
• Positive test for Hepatitis B, C, or cytomegalovirus (CMV),
• Use of immunosuppressive medication,
• Vaccination within 4 weeks of the baseline visit,
• Major surgery within 8 weeks of the baseline visit,
• Previous lymphoid irradiation or bone marrow transplant,
• Subjects at risk for diverticulitis,
• Any laboratory test result that, in the opinion of the overseeing physician (Dr. Frech) might place a participant at unacceptable risk.

Related Conditions & MeSH terms

• Aging
• Cardiovascular Diseases
• Inflammation

Intervention

Other:
• Placebo
Placebo injection at day one and day fourteen.

Drug:
• Abatacept 10 mg/kg
Abatacept injection at day twenty eight and day forty two.

Locations

Country	Name	City	State
n/a

Sponsors (2)

Lead Sponsor	Collaborator
University of Utah	National Institute on Aging (NIA)

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in brachial arterial diameter after abatacept injection.		7 weeks
Primary	Change in brachial arterial flow rate after abatacept injection.		7 weeks
Secondary	Change in pulse wave velocity as measured by doppler ultrasound after abatacept injection.		7 weeks
Secondary	Change in proportion of memory T-Cells after abatacept injection		7 weeks
Secondary	Change in proportion of inflammatory biomarker Tumour Necrosis Factor alpha (TNF-a) after abatacept injection		7 weeks
Secondary	Change in proportion of inflammatory biomarker Interferon gamma (IFN-?) after abatacept injection		7 weeks
Secondary	Change in proportion of inflammatory biomarker interleukin 10 (IL-10) after abatacept injection		7 weeks
Secondary	Change in proportion of inflammatory biomarker interleukin 17 (IL-17) after abatacept injection		7 weeks
Secondary	Change in proportion of inflammatory biomarker forkhead box P3 (FoxP3) after abatacept injection		7 weeks
Secondary	Change in proportion of inflammatory biomarker perforin after abatacept injection		7 weeks