Impact of Chemokine Receptor 5 (CCR5) Inhibition on Sarcoidosis Immunophenotypes

Study Overview
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Brief Summary
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The study hypothesizes that inhibition of the receptor CCR5 by maraviroc will diminish inflammation in patients with sarcoidosis. Subjects with active sarcoidosis will first undergo bronchoscopy with bronchoalveolar lavage to recover lung immune cells for baseline analysis. They will then receive the drug maraviroc for 6 weeks duration. They will then undergo a repeat bronchoscopy with bronchoalveolar lavage to recover lung immune cells for analysis following maraviroc treatment.

Detailed Description
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The investigators hypothesize that inhibition of CCR5 by maraviroc may have a beneficial immunomodulatory effect on the granulomatous inflammation of pulmonary sarcoidosis. The specific aim of this proposal is the investigate the effect of CCR5 inhibition on the trafficking of mononuclear cells to the lung, skin, peripheral blood in subjects with active sarcoidosis exposed to the CCR5 inhibitor, maraviroc. A second aim will be to isolate by cell sorting cluster of differentiation 4 (CD4)+CCR5+ T cells for amplified gene expression profiling before and after CCR5 inhibition, experiments the investigators believe will elucidate genes associated with downstream activation and inhibition of CCR5 receptor function.

Official Title
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An Interventional Study of the Effect of CCR5 Inhibition With Maraviroc on Immune Cells in the the Lung and in Peripheral Blood of Patients With Sarcoidosis

Conditions
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Sarcoidosis

Intervention / Treatment
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* Drug: all subjects will receive maraviroc 300mg orally twice a day for 6 weeks
* Procedure: Bronchoscopy with bronchoalveolar lavage
* Procedure: venipunctures
* Procedure: Skin biopsy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically proven sarcoidosis from any site (noncaseating granulomas without other causes). Diagnosis of active sarcoidosis (Sec. 5.5.4.t) clinical stage II by Chest X-ray (CXR). Forced Vital Capacity (FVC) >45% and Diffusing Capacity for Carbon Monoxide (DLCO) >50% of predicted values. Evidence of active sarcoidosis (see criteria above) Able and willing to complete all study procedures (e.g., bronchoscopy, post-drug surveillance) Age: 18+ years old (prevalence greatest in young adults; pediatric maraviroc safety not established). Not on immunosuppression for sarcoidosis at the time of recruitment, (e.g., steroids, tumor necrosis factor alpha (TNF-a) blockade) Liver function (transaminases, bilirubin), coagulation (International Normalized Ratio (INR), partial thromboplastin time (PTT), platelet count), blood urea nitrogen (BUN), creatinine, and white blood count (WBC) within normal limits. If female: negative pregnancy test, agreement to use reliable contraception if of childbearing potential 30 days prior and for 30 days after study completion (drug safety during pregnancy not established). Negative HIV and HBsAg tests Exclusion Criteria: Diagnosis of infection based upon clinical evaluation and/or microbial testing. The diagnosis of any disease involving the heart, lungs, liver (HVC), kidney, hematologic, endocrine, or Gl systems which, in the judgment of the PI, would pose an undue risk to the subject if they participated in this study. This includes but is not limited to diabetes, uncontrolled hypertension, liver disease (HVC), or history of malignancy. Medications that will either inhibit or induce CYP3A4 (including St John's Wort)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: sarcoidosis stage II<br>All subjects with active stage II sarcoidosis with or without skin disease will receive the drug maraviroc 300mg to be taken orally twice a day for 6 weeks duration. | Drug: all subjects will receive maraviroc 300mg orally twice a day for 6 weeks<br> <br> * Other names: selzentry;Procedure: Bronchoscopy with bronchoalveolar lavage<br>* Bronchoscopy employs a flexible instrument that is inserted into the trachea and proximal airways after topical anesthesia. Bronchoalveolar lavage involves the instillation of saline solution through the bronchoscope into the airways followed by recovery under suction to collects lung fluid containing cells and proteins.<br>Procedure: venipunctures<br>* Venipunctures will be performed at study entry, after two weeks, and at the end of the study to collect blood for research studies and safety laboratories.<br>Procedure: Skin biopsy<br>* For subjects with sarcoidosis skin lesions, an optional skin biopsy specimen may be collected for research studies.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total Cell Count and Differentials in Blood and Bronchoalveolar Lavage Fluid Pre- and Post Maraviroc | General indicators of inflammation following chemokine receptor 5 (CCR5) inhibition in blood and bronchoalveolar lavage | 6 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mononuclear Cell (MNC) Activation and T-cell Differentiation | MNC activation and T-cell differentiation before and after CCR5 inhibition. | 6 weeks | 
| Chemokine Receptor 5 (CCR5) Expression Among These Immune Effector Cells | CCR5 expression among these immune effector cells before and after CCR5 inhibition. | 6 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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sarcoidosis, CCR5 inhibition, maraviroc