Differential roles of VLA-4(CD49d/CD29) and LFA-1(CD11a/CD18) integrins and E- and P-selectin during developing and established active or adoptively transferred adjuvant arthritis in the rat.
The role of the integrins VLA-4 and LFA-1 and of the selectin adhesion molecules in autoimmune arthritis was investigated. Adjuvant arthritis was induced in Lewis rats by active immunization (s.c.) with Mycobacterium butyricum or by adoptive transfer of immune T cells. With active adjuvant arthritis, Lewis rats develop maximal polyarticular joint inflammation and migration of radiolabelled (111In and 51Cr) blood neutrophils and monocytes to the joints 14 days post Mycobacterium butyricum immunization. Using blocking monoclonal antibodies we osbserved that at this stage monocyte recruitment was dependent (85%) on P-selectin plus VLA-4 (alpha4B1) and neutrophil recruitment depended (> 80%) on P-selectin plus LFA-1 (CD11a/CD18). E-selectin played a minimal role in inflammatory cell recruitment to the already inflamed joint. In contrast, during the development of active adjuvant arthritis, blockade of P-selectin beginning at day 5 post-immunization had no effect on subsequent arthritis. However, E-selectin blockade at this stage reduced arthritic scores by 70% (P < 0.01) and combined E-selectin plus VLA-4 blockade prevented development of arthritis. Either treatment nearly abolished neutrophil and monocyte recruitment to joints at day 14 and prevented cartilage damage. VLA-4 blockade alone was less effective. Adoptive T-cell transfer of adjuvant arthritis to naive rats employed spleen/lymph node lymphocytes from Mycobacterium butyricum immunized rats stimulated with Concanavalin A in vitro (48 h). E-selectin +/- P-selectin blockade had no effect on the development of adoptive arthritis. However, VLA-4 integrin blockade inhibited adoptive arthritis severity by 55% (P < 0.01). LFA-1 blockade had no effect. In adoptive adjuvant arthritis, inhibition of arthritis clinically and by histology was essentially complete (> 90%) when E- and P-selectin blockade was combined with VLA-4 blockade. Thus, in the development of actively induced arthritis E-selectin plays an important role, likely mediating early antigen reactive T-cell recruitment to joints. In contrast, VLA-4 and multiple selectin mechanisms are involved in arthritis induction by ex vivo restimulated arthritogenic T cells. Furthermore, in actively induced adjuvant arthritis, P- and E-selectin and VLA-4 are differently important in the initiation of arthritis, and at the time of fully developed joint inflammation.
Issekutz
Andrew C
AC
Departments of Pediatrics, Pathology and Microbiology-Immunology, Dalhousie University, Halifax, Nova Scotia, Canada. Andrew.Issekutz@iwk.nshealth.ca
Nakazato
Satoru
S
Issekutz
Thomas B
TB
D019264:Adoptive Transfer; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D001169:Arthritis, Experimental / Q000276:immunology* / Q000628:therapy; D019040:E-Selectin / Q000276:immunology / Q000502:physiology*; D039041:Integrin alpha4beta1 / Q000276:immunology / Q000502:physiology*; D007596:Joints / Q000276:immunology / Q000473:pathology; D016169:Lymphocyte Function-Associated Antigen-1 / Q000276:immunology / Q000502:physiology*; D008297:Male; D019007:P-Selectin / Q000276:immunology / Q000502:physiology*; D051381:Rats; D011917:Rats, Inbred Lew; D013601:T-Lymphocytes / Q000637:transplantation
D000911:Antibodies, Monoclonal; D019040:E-Selectin; D039041:Integrin alpha4beta1; D016169:Lymphocyte Function-Associated Antigen-1; D019007:P-Selectin