In vivo migration of radiolabelled lymphocytes in rheumatoid synovial tissue engrafted in SCID mice: implication of beta 2 and beta 7-integrin.
OBJECTIVE
Integrin-adressin binding is a critical step in lymphocyte attachment to target tissues. The lymphocyte function associated antigen (LFA-1)/intercellular adhesion molecule-1 (ICAM-1) pathway has been shown to be involved in the homing of lymphocytes to arthritic joints in animal models. The mucosal recognition system [alpha E beta 7/E-cadherin, alpha 4 beta 7/mucosal vascular adressin cellular adhesion molecule 1 (MADCAM-1)] has been implicated in the autoimmune process of nonobese diabetic mice and in rheumatoid arthritis (RA). We developed a model for in vivo study of radiolabelled lymphocyte circulation and attachment to human engrafted rheumatoid synovium, and studied the involvement of LFA-1 and alpha E beta 7 integrin.


METHODS
We engrafted human RA or osteoarthritis (OA) synovium subcutaneously in 6-week-old SCID/CB17 mice. Three weeks later, we injected intraperitoneally 20 x 10(6) human peripheral blood lymphocytes (PBL) labelled with 3 mCi 99mtechnetium hexamethyl propylenamine oxime. A mouse total body scintigraphy was obtained 20 h postinjection. The same protocol was performed after pretreatment of the PBL with monoclonal antibodies (Mab) against CD11a (25-3) or against alpha E beta 7 human mucosyl lymphocyte marker 1.


RESULTS
PBL migrated in the rheumatoid synovial graft 20 h postinjection (activity in the region of interest of the graft: 7699 +/- 4383 cpm/200 pixel or 4.43 +/- 2.65% of initial activity) versus OA engrafted synovial tissue (1453 +/- 1137 or 0.74 +/- 0.6% of initial activity), p = 0.007. The homing to the engrafted rheumatoid synovial tissue of PBL from healthy subjects was not significantly different from the migration of PBL from patients with RA. A Mab against alpha E beta 7 significantly decreased lymphocyte attachment to rheumatoid synovial tissue (3094 +/- 3808 cpm/200 pixel or 2.65 +/- 2.4% of injected activity), p < 0.03. The same results were obtained with Mab against CD11a (5007 +/- 4190 cpm/200 pixel or 2.27 +/- 1.2%), p < 0.01. Our results show increased blood lymphocytes homing to rheumatoid synovial tissue engrafted in SCID mice versus OA tissue.


CONCLUSIONS
The data suggest that both LFA-1 and mucosal recognition integrin alpha E beta 7 are involved in lymphocyte binding to target tissues in RA.
Jorgensen
C
C
Service d'Immuno-Rhumatologie, Centre Gui-de-Chauliac, France.
Couret
I
I
Hellier
I
I
Bologna
C
C
Canovas
F
F
Brochier
J
J
Reme
T
T
Sany
J
J
D000818:Animals; D015703:Antigens, CD / Q000276:immunology / Q000502:physiology; D001172:Arthritis, Rheumatoid / Q000503:physiopathology*; D018821:CD18 Antigens / Q000502:physiology*; D002448:Cell Adhesion; D002465:Cell Movement; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D039641:Integrin beta Chains; D016023:Integrins / Q000502:physiology*; D008214:Lymphocytes / Q000000981:diagnostic imaging / Q000502:physiology*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D010003:Osteoarthritis / Q000503:physiopathology*; D011877:Radionuclide Imaging; D013583:Synovial Membrane / Q000502:physiology / Q000637:transplantation*
D015703:Antigens, CD; D018821:CD18 Antigens; D039641:Integrin beta Chains; D016023:Integrins; C091368:integrin beta7