Regulatory T cells control the transition from acute into chronic inflammation in glucose-6-phosphate isomerase-induced arthritis.
OBJECTIVE
Glucose-6-phosphate isomerase (G6PI)-induced arthritis is a spontaneously remitting experimental arthritis model. It was hypothesised that regulatory T cells (Tregs) are involved in remission and their role in G6PI-induced arthritis was investigated.


METHODS
Tregs were depleted by injection of anti-CD25 before immunisation of DBA/1 mice with G6PI. The severity of arthritis was assessed clinically and histologically and the number and function of G6PI-specific T helper (Th) cells were determined by flow cytometry. Th cells and monocytes/macrophages were depleted using anti-CD4 or clodronate-containing liposomes.


RESULTS
Injection of anti-CD25 depleted Tregs transiently. Normal numbers of Tregs were restored 5 weeks after G6PI immunisation. Whereas arthritis started to resolve in control mice 3 weeks after immunisation with G6PI, severe arthritis was still present in the anti-CD25-treated mice 12 weeks after immunisation. The most striking ex vivo correlate of non-remitting arthritis was a strong increase in G6PI-specific Th cells 3 days after G6PI immunisation. This difference between treated and control mice declined at later time points. Depletion of CD4 cells ameliorated arthritis in controls but not in anti-CD25-treated mice. In contrast, clodronate-containing liposomes were an effective treatment in both groups.


CONCLUSIONS
Tregs control the transition from acute self-limiting to non-remitting destructive G6PI-induced arthritis already in the preclinical disease stage. Once established, non-remitting destructive arthritis is not controlled by restoration of normal Treg numbers. These findings question the rationale of therapeutic approaches augmenting Treg number or function in established arthritis.
Frey
Oliver
O
Institut für Immunologie, Universitätsklinikum Jena, Leutragraben, Germany.
Reichel
Andreas
A
Bonhagen
Kerstin
K
Morawietz
Lars
L
Rauchhaus
Una
U
Kamradt
Thomas
T
D000208:Acute Disease; D000818:Animals; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002908:Chronic Disease; D018450:Disease Progression; D005956:Glucose-6-Phosphate Isomerase / Q000276:immunology; D007114:Immunization; D007074:Immunoglobulin G / Q000096:biosynthesis; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology; D051379:Mice; D008811:Mice, Inbred DBA; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
D007074:Immunoglobulin G; D053645:Interleukin-2 Receptor alpha Subunit; D005956:Glucose-6-Phosphate Isomerase