Suppression of collagen-induced arthritis by single administration of poly(lactic-co-glycolic acid) nanoparticles entrapping type II collagen: a novel treatment strategy for induction of oral tolerance.
OBJECTIVE
Poly(lactic-co-glycolic acid) (PLGA), a biodegradable polymer, is a carrier for drug delivery systems. This study was undertaken to investigate the tolerogenic effect of single administration of PLGA entrapping type II collagen (CII) on the development of collagen-induced arthritis (CIA).


METHODS
The biophysical properties of PLGA nanoparticles entrapping CII (PLGA-CII) were investigated by in vitro release testing of CII, immunohistochemistry analysis, and electron microscopy. PLGA-CII was fed singly to animals 14 days before immunization, and the effect on joint inflammation was assessed. Circulating IgG anti-CII antibodies and T cell responses to CII in draining lymph nodes were assayed by enzyme-linked immunosorbent assay and (3)H-thymidine incorporation assay, respectively. The expression of messenger RNA (mRNA) for transforming growth factor beta (TGFbeta) and tumor necrosis factor alpha (TNFalpha) was determined by reverse transcriptase-polymerase chain reaction.


RESULTS
The in vitro release test showed that CII was slowly discharged from PLGA-CII over a period of a month. After single administration of PLGA-CII, numerous particles approximately 300 nm in size were detectable in Peyer's patches, by electron microscopy and immunohistochemical staining for CII, 14 days after the original feeding. Mice fed a single dose of PLGA containing 40 microg of CII had significantly reduced values for incidence and severity of arthritis, serum IgG anti-CII antibodies, and CII-specific T cell proliferation as compared with mice fed solvent alone, those fed 6 doses of 20 microg CII alone, and those fed a single dose of PLGA alone. PLGA-CII was also able to suppress CIA after disease onset. Moreover, PLGA-CII-fed mice showed a higher level of TGFbeta mRNA expression in Peyer's patches, but a lower level of TNFalpha mRNA expression in draining lymph nodes, compared with the other groups of mice.


CONCLUSIONS
Our data show that PLGA may serve as a powerful vehicle to promote the tolerance effect of oral CII and that single administration of PLGA-CII may hold promise as a new treatment strategy in rheumatoid arthritis.
Kim
Wan-Uk
WU
The Catholic University of Korea, Seoul, Republic of South Korea.
Lee
Woo-Kyoung
WK
Ryoo
Jae-Woong
JW
Kim
Seung-Hoon
SH
Kim
Jin
J
Youn
Jeehee
J
Min
So-Youn
SY
Bae
Eui-Young
EY
Hwang
Sue-Yun
SY
Park
Sung-Hwan
SH
Cho
Chul-Soo
CS
Park
Jong-Sang
JS
Kim
Ho-Youn
HY
D000818:Animals; D001169:Arthritis, Experimental / Q000628:therapy*; D001172:Arthritis, Rheumatoid / Q000628:therapy; D015551:Autoimmunity / Q000187:drug effects; D001672:Biocompatible Materials / Q000737:chemistry / Q000494:pharmacology*; D002417:Cattle; D024043:Collagen Type II / Q000737:chemistry*; D004195:Disease Models, Animal; D018450:Disease Progression; D015870:Gene Expression / Q000276:immunology; D066298:In Vitro Techniques; D019344:Lactic Acid / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D008854:Microscopy, Electron; D010316:Particle Size; D010581:Peyer's Patches / Q000276:immunology / Q000648:ultrastructure; D011100:Polyglycolic Acid / Q000737:chemistry / Q000494:pharmacology*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011108:Polymers / Q000737:chemistry / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D016212:Transforming Growth Factor beta / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
D001672:Biocompatible Materials; D024043:Collagen Type II; D011108:Polymers; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid