Intratracheal administration to the lung enhances therapeutic benefit of an MBP peptide in the treatment of murine experimental autoimmune encephalomyelitis.
The treatment of autoimmune diseases by targeted down-regulation of autoantigen-specific cells has been accomplished by the administration of high doses of autoantigen. We performed direct comparisons between injection of myelin basic protein peptide and administration by several nonparenteral routes to determine whether route impacted benefit in the treatment of murine allergic encephalomyelitis, a model for multiple sclerosis. The range of effective peptide doses spanned over 1000-fold, and route of delivery played a major role in determining optimal dose. The oral route of administration was the least effective, requiring at least 50- to 100-fold more antigen than subcutaneous injection, which in turn required at least 10-fold more antigen than delivery of peptide to the lung using an intratracheal instillation. Intratracheal delivery was also considerably more effective than inhalation of peptide, and, unlike inhalation, resulted in obvious penetration of delivered material deep into the lung. The increase in therapeutic efficacy did not appear to result from slower systemic delivery of antigen. Accumulation of peptide on antigen presenting cells in the spleen and in the brain was less efficient using the intratracheal route of administration compared to subcutaneous injection, implicating a special role for the lung microenvironment in the induction of immune nonresponsiveness.
Pietropaolo
M
M
ImmuLogic Pharmaceutical Corporation, Waltham, MA 02451, USA.
Olson
C D
CD
Reiseter
B S
BS
Kasaian
M T
MT
Happ
M P
MP
D000280:Administration, Inhalation; D000284:Administration, Oral; D000818:Animals; D000938:Antigen-Presenting Cells / Q000187:drug effects; D001324:Autoantigens / Q000008:administration & dosage; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy*; D005260:Female; D007279:Injections, Subcutaneous; D007442:Intubation, Intratracheal; D008168:Lung / Q000187:drug effects; D051379:Mice; D004676:Myelin Basic Protein / Q000008:administration & dosage* / Q000276:immunology / Q000493:pharmacokinetics; D010446:Peptide Fragments / Q000008:administration & dosage; D013810:Therapeutic Equivalency
D001324:Autoantigens; D004676:Myelin Basic Protein; D010446:Peptide Fragments; C405723:myelin basic protein Ac1-11(4Y)