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Safety and Immunological Evaluation of Interleukin-21 Plus Anti-α4β7 mAb Combination Therapy in Rhesus Macaques
- Source :
- Frontiers in Immunology, Vol 11 (2020), Frontiers in Immunology
- Publication Year :
- 2020
- Publisher :
- Frontiers Media SA, 2020.
-
Abstract
- Human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) infections compromise gut immunological barriers, inducing high levels of inflammation and a severe depletion of intestinal CD4+ T cells. Expression of α4β7 integrin promotes homing of activated T cells to intestinal sites where they become preferentially infected; blockade of α4β7 with an anti-α4β7 monoclonal antibody (mAb) prior to infection has been reported to reduce gut SIV viremia in rhesus macaques (RMs). Interleukin-21 (IL-21) administration in antiretroviral therapy-treated, SIV-infected RMs reduces gut inflammation and improves gut integrity. We therefore hypothesized that the combination of IL-21 and anti-α4β7 mAb therapies could synergize to reduce inflammation and HIV persistence. We co-administered two intravenous doses of rhesus anti-α4β7 mAb (50 mg/kg) combined with seven weekly subcutaneous infusions of IL-21–IgFc (100 μg/kg) in four healthy, SIV-uninfected RMs to evaluate the safety and immunological profiles of this intervention in blood and gut. Co-administration of IL-21 and anti-α4β7 mAb showed no toxicity at the given dosages as assessed by multiple hematological and chemical parameters and did not alter the bioavailability of the therapeutics or result in the generation of antibodies against the anti-α4β7 mAb or IL-21–IgFc. Upon treatment, the frequency of CD4 memory T cells expressing β7 increased in blood and decreased in gut, consistent with an inhibition of activated CD4 T-cell homing to the gut. Furthermore, the frequency of T cells expressing proliferation and immune activation markers decreased in blood and, more profoundly, in gut. The combined IL-21 plus anti-α4β7 mAb therapy is well-tolerated in SIV-uninfected RMs and reduces the gut homing of α4β7+ CD4 T cells as well as the levels of gut immune activation.
- Subjects :
- lcsh:Immunologic diseases. Allergy
0301 basic medicine
Integrins
anti-α4β7
Combination therapy
macaques
medicine.drug_class
Immunology
Biological Availability
Viremia
Inflammation
medicine.disease_cause
Monoclonal antibody
immune activation
rhesus macaques
03 medical and health sciences
Interleukin 21
0302 clinical medicine
Isoantibodies
IL-21
Animals
Humans
Immunology and Allergy
Medicine
Original Research
biology
business.industry
Interleukins
Immunity
Antibodies, Monoclonal
Simian immunodeficiency virus
medicine.disease
Macaca mulatta
Immunoglobulin Fc Fragments
Killer Cells, Natural
T- cell homing
combined immune intervention
030104 developmental biology
Leukocytes, Mononuclear
biology.protein
Drug Therapy, Combination
medicine.symptom
Antibody
lcsh:RC581-607
business
Biomarkers
030215 immunology
Homing (hematopoietic)
Subjects
Details
- ISSN :
- 16643224
- Volume :
- 11
- Database :
- OpenAIRE
- Journal :
- Frontiers in Immunology
- Accession number :
- edsair.doi.dedup.....d47375c157ca59428f063220c0d46cf4