CD25+ cell depletion hastens the onset of severe disease in collagen-induced arthritis.
OBJECTIVE
CD4+,CD25+ T regulatory cells may offer opportunities to intervene in the course of autoimmune disease. We wished to evaluate their potential for influencing systemic and chronic joint inflammation by investigating their involvement in collagen-induced arthritis (CIA).


METHODS
We depleted DBA/1 mice of CD25+ regulatory cells by injection of a depleting monoclonal antibody specific for CD25 14 days before a single immunization with type II collagen (CII) in Freund's complete adjuvant. CD4+,CD25+ T cells were adoptively transferred to some groups of mice during immunization. Mice were then scored for signs of arthritis, and blood was taken periodically to measure the amounts of CII-specific antibodies. Splenocytes of treated mice were examined in vitro to determine the effects of depletion on proliferation to CII and control antigens.


RESULTS
CD25+ cell-depleted DBA/1 mice had significantly more severe disease than control mice following collagen immunization. The magnified severity was also accompanied by higher antibody titers against collagen, and in vitro tests showed increased proliferation of collagen-specific T cells. Adoptively transferring CD4+,CD25+ T cells into depleted mice was shown to reverse the heightened severity. Control mice, which were depleted and immunized with the neoantigen keyhole limpet hemocyanin (KLH), had neither an increased antibody response toward KLH nor an augmented proliferative response, indicating that CD25+ cell depletion preferentially affects immunity against self antigen.


CONCLUSIONS
These results establish a link between CD4+,CD25+ regulatory cells and CIA and provide a rationale for investigating CD4+,CD25+ T regulatory cells in the treatment and prevention of arthritis.
Morgan
Mary E
ME
Leiden University Medical Center, Leiden, The Netherlands. M.E.Morgan@lumc.nl
Sutmuller
Roger P M
RP
Witteveen
Hendrik J
HJ
van Duivenvoorde
Leonie M
LM
Zanelli
Eric
E
Melief
Cornelis J M
CJ
Snijders
Alies
A
Offringa
Rienk
R
de Vries
René R P
RR
Toes
René E M
RE
D019264:Adoptive Transfer; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000494:pharmacology; D001169:Arthritis, Experimental / Q000276:immunology* / Q000378:metabolism / Q000503:physiopathology; D015704:CD4 Antigens / Q000096:biosynthesis / Q000276:immunology; D002455:Cell Division; D024043:Collagen Type II / Q000276:immunology / Q000494:pharmacology; D004487:Edema / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005552:Forelimb / Q000473:pathology; D005620:Freund's Adjuvant / Q000276:immunology / Q000494:pharmacology; D006433:Hemocyanins / Q000276:immunology / Q000494:pharmacology; D006614:Hindlimb / Q000473:pathology; D007114:Immunization; D008212:Lymphocyte Depletion; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D051381:Rats; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis / Q000276:immunology*; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation
D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D024043:Collagen Type II; D015375:Receptors, Interleukin-2; D005620:Freund's Adjuvant; D006433:Hemocyanins; C032808:keyhole-limpet hemocyanin