title: An Update on the Use of Immunomodulators in Primary Immunodeficiencies.
abstract: The genomic revolution in the past decade fuelled by breathtaking advances in sequencing technologies has defined several new genetic diseases of the immune system. Many of these newly characterized diseases are a result of defects in genes involved in immune regulation. The discovery of these diseases has opened a vista of new therapeutic possibilities. Immunomodulatory agents, a hitherto unexplored therapeutic option in primary immunodeficiency diseases have been tried in a host of these newly described maladies. These agents have been shown conclusively to favorably modulate immune responses, resulting in abatement of clinical manifestations both in experimental models and patients. While some of the treatment options have been approved for therapeutic use or have been shown to be of merit in open-label trials, others have been shown to be efficacious in a handful of clinical cases, animal models, and cell lines. Interferon γ is approved for use in chronic granulomatous disease (CGD) to reduce the burden of infection and and has a good long-term efficacy. Recombinant human IL7 therapy has been shown increase the peripheral CD4 and CD8 T cell counts in patients with idiopathic CD4. Anti-IL1 agents are approved for the management of cryopyrin-related autoinflammatory syndrome, and their therapeutic efficacy is being increasingly recognized in other autoinflammatory syndromes and CGD. Mammalian target of rapamycin (mTOR) inhibitors have been proven useful in autoimmune lymphoproliferative syndrome (ALPS) and in IPEX syndrome. Therapies reported to be potential use in case reports include abatacept in CTLA4 haploinsufficiency and LRBA deficiency, ruxolitinib in gain-of-function STAT1, tocilizumab in gain-of-function STAT3 defect, mTOR inhibitors in PIK3CD activation, magnesium in XMEN syndrome, and pioglitazone in CGD. Treatment options of merit in human cell lines include interferon α and interferon β in TLR3 and UNC-93B deficiencies, anti-interferon therapy in SAVI, and Rho-kinase inhibitors in TTC7A deficiency. Anti-IL17 agents have show efficacy in animal models of leukocyte adhesion defect (LAD) and ALPS. This topical review explores the use of various immunomodulators and other biological agents in the context of primary immunodeficiency and autoinflammatory diseases.
authors.affiliation: Pediatric Allergy and Immunology Unit, Advanced Pediatrics Centre, PGIMER, Chandigarh, India.
authors.forename: Pandiarajan
authors.initials: P
authors.lastname: Vignesh
authors.affiliation: Pediatric Allergy and Immunology Unit, Advanced Pediatrics Centre, PGIMER, Chandigarh, India. rawatamit@yahoo.com.
authors.forename: Amit
authors.identifier: http://orcid.org/0000-0002-5875-2892
authors.initials: A
authors.lastname: Rawat
authors.affiliation: Pediatric Allergy and Immunology Unit, Advanced Pediatrics Centre, PGIMER, Chandigarh, India.
authors.forename: Surjit
authors.initials: S
authors.lastname: Singh
mesh_terms: D000818:Animals; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000188:drug therapy*; D007155:Immunologic Factors / Q000627:therapeutic use*
chemical_list: D007155:Immunologic Factors
keywords: Autoinflammatory disorders; Immunomodulators; Monoclonal antibodies; Primary immunodeficiencies