Prevention of collagen-induced arthritis (CIA) by treatment with polyethylene glycol-conjugated type II collagen; distinct tolerogenic property of the conjugated collagen from the native one

Abstract

SUMMARYAdministration of a soluble protein into animals prior to challenge immunization induces immunological tolerance which is specific for the protein. In addition, chemical modification of proteins with polyethylene glycol (PEG) has been reported to convert the immunogenic proteins to become tolerogenic. However, differences in tolerogenic properties between PEG-modified proteins and the native counterparts have never been analysed. The ability of PEG-conjugated type II collagen (PEG-CII) to attenuate CIA, an animal model for rheumatoid arthritis, was compared with the native unconjugated CII. Groups of DBA/1 J mice were treated weekly with i.p. injections with PEG-CII, native CII, or vehicle alone for 3 weeks, before they were challenged with CII in adjuvants. The induction of tolerance was confirmed in both PEG-CII-and CII-pretreated mice when suppression of lymph node T cell proliferation in response to CII was noted. The degrees of suppression of T cell proliferation were comparable between the two pretreated groups. However, induction of arthritis and production of IgG anti-CII antibody were more markedly suppressed in PEG-CII-pretreated mice than in native CII-pretreated mice, although the severity of arthritis and antibody levels in the latter group were also lower than in control mice. IgG2a and IgG2b antibody levels were equally suppressed in the two pretreated groups, whereas the IgG1 level was significantly lower in the PEG-CII-pretreated group than in the native CII-pretreated group. The results provide the first evidence that attachment of PEG to CII renders the protein more tolerogenic.

Coupling Reaction and Properties of Poly(ethylene glycol)-linked Phospholipases A2

“…11) In this context, it has been reported that the attachment of PEG to type II collagen alters the immunological property of the protein to render it more tolerogenic. 30) The results presented herein, together with the accumulated evidence, open the possibility to use these PEG-PLA2 adducts to further explore on the immunogenicity of secretory phospholipases.…”

Monomethoxypolyethylene Glycol-Modified Cardiac Myosin Treatment Blocks the Active and Passive Induction of Experimental Autoimmune Myocarditis

“…The tolerance induced by mPEG-Ag treatment is potentially mediated by the anergy of Ag-specific T cells or by the generation of suppressor T (Ts) cells. [5][6][7][8][9][14][15][16] With regard to the role of mPEG-CM, we found that mPEG-CM pretreatment was able to suppress EAM induced by the adoptive transfer of CM-primed splenocytes. Thus, in this experiment, anergy is not the case.…”

“…6 mPEG-modified Ags induce particularly strong suppressive effects if administered prior to the injection of the unmodified Ag. It now appears that the development of several experimental autoimmune diseases, including experimental autoimmune myasthenia gravis, 7 experimental immune mediated blepharoconjunctivitis, 8 and collagen-induced arthritis, 9 can be suppressed by treatment with mPEG-Ag conjugates. In the present study, we extended our investigation to examine whether or not injection of mice with the mPEG-CM conjugate also suppresses the development of EAM.…”

Extended blood half-life of monomethoxypolyethylene glycol-conjugated hen lysozyme is a key parameter controlling immunological tolerogenicity

“…Cultures for a lymph node T cell proliferation assay were set up according to Adorini et al [12], and the proliferation was measured after 96 h using a colorimetric assay based on tetrazolium salt, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), as described [13]. Antigen-specific serum IgG titers were measured using enzyme-linked immunosorbent assay (ELISA), as described elsewhere [8,9]. Measurement of protein concentrations in blood circulation.…”

“…preinjection of adult mice with the mPEG protein effectively tolerizes immune responses against subsequent injection of the unconjugated counterpart. We have proposed that mPEG-type II collagen and mPEG-hen egg lysozyme (HEL) are effective in tolerizing both T helper type 1 (Th1) and T helper type 2 (Th2) immune responses, whereas the native counterpart suppresses Th1-type responses but tends to spare Th2-type responses [8,9]. This means that mPEG proteins are effective in suppressing both cell-mediated and humoral immune responses against the proteins, while the conventional protocol for tolerance induction is not effective in suppressing the latter response.…”