The beta 2-adrenergic agonist salbutamol potentiates oral induction of tolerance, suppressing adjuvant arthritis and antigen-specific immunity.
Therapeutic protocols for treating autoimmune diseases by feeding autoantigens during the disease process have not been very successful to date. In vitro it has been shown that beta-adrenergic agonists inhibit pro-inflammatory cytokine production and up-regulate anti-inflammatory cytokine production. We hypothesized that the protective effect of oral administration of Ag would be enhanced by oral coadministration of the beta(2)-adrenergic agonist salbutamol. Here we demonstrate that oral administration of salbutamol in combination with the Ag mycobacterial 65-kDa heat shock protein increased the efficacy of disease-suppressive tolerance induction in rat adjuvant arthritis. To study the mechanism of salbutamol in more detail, we also tested oral administration of salbutamol in an OVA tolerance model in BALB/c mice. Oral coadministration of OVA/salbutamol after immunization with OVA efficiently suppressed both cellular and humoral responses to OVA. Coadministration of salbutamol was associated with an immediate increase in IL-10, TGF-beta, and IL-1R antagonist in the intestine. The tolerizing effect of salbutamol/OVA was maintained for at least 12 wk. At this time point IFN-gamma production in Ag-stimulated splenocytes was increased in the OVA/salbutamol-treated animals. In conclusion, salbutamol can be of great clinical benefit for the treatment of autoimmune diseases by promoting oral tolerance induction.
Cobelens
Pieter M
PM
Department of Immunology, Laboratory for Psychoneuroimmunology, University Medical Center Utrecht, The Netherlands.
Kavelaars
Annemieke
A
Vroon
Anne
A
Ringeling
Marion
M
van der Zee
Ruurd
R
van Eden
Willem
W
Heijnen
Cobi J
CJ
D000276:Adjuvants, Immunologic / Q000008:administration & dosage* / Q000627:therapeutic use; D000284:Administration, Oral; D000318:Adrenergic beta-Agonists / Q000008:administration & dosage* / Q000627:therapeutic use; D000420:Albuterol / Q000008:administration & dosage* / Q000627:therapeutic use; D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology* / Q000517:prevention & control*; D001426:Bacterial Proteins; D002478:Cells, Cultured; D018834:Chaperonin 60; D018833:Chaperonins / Q000008:administration & dosage; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D004032:Diet; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology; D004338:Drug Combinations; D004357:Drug Synergism; D000939:Epitopes / Q000276:immunology*; D005620:Freund's Adjuvant / Q000008:administration & dosage; D007108:Immune Tolerance / Q000187:drug effects / Q000276:immunology*; D007113:Immunity, Innate / Q000187:drug effects; D007114:Immunization; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D007274:Injections, Intraperitoneal; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D051381:Rats; D011917:Rats, Inbred Lew; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology
D000276:Adjuvants, Immunologic; D000318:Adrenergic beta-Agonists; D001426:Bacterial Proteins; D018834:Chaperonin 60; D016207:Cytokines; D004338:Drug Combinations; D000939:Epitopes; D007166:Immunosuppressive Agents; C074119:heat-shock protein 65, Mycobacterium; D010047:Ovalbumin; D005620:Freund's Adjuvant; D018833:Chaperonins; D000420:Albuterol