[Role of cell migration in the pathogenesis of rheumatoid arthritis: in vivo studies in SCID mice transplanted with human synovial membrane].
OBJECTIVE
Adhesion mechanisms play a central role in the recruitment of leukocytes which characteristically infiltrate rheumatoid synovium. Therefore, we adapted an animal model, in which human rheumatoid synovium was transplanted into severe combined immunodeficient (SCID) mice, to study the effects of Tumor Necrosis Factor-alpha (TNF-alpha) in modulatine leukocyte migration and to investigate the chemotactic potential of Stromal Derived Factor-1 alpha (SDF-1 alpha).


METHODS
Human synovium samples, obtained from patients undergoing joint replacement, were divided into two parts. One was analysed by immunohistology and the other was implanted subcutaneously into SCID mice under general anaesthesia. Four weeks post-transplantation, grafts were injected with optimal dose of SDF-1, TNF-alpha or saline (negative control). At the same time, animals were injected iv with fluorescently labelled cells. 48 hours later mice were sacrificed and grafts removed for cryo-hystology. The number of cells migrating to the grafts was determined by UV-microscopy and the results expressed as cells per high power field.


CONCLUSIONS
In these studies we provide the evidence that: 1) the animal model, in which human tissues are grafted into SCID mice, can be used to study cell migration under controlled experimental conditions; 2) direct intragraft injection of TNF-alpha increases lymphocytes migration and up-regulates the expression of human adhesion molecules (CAMs) and 3) SDF-1 alphainjected intragraft increases the migration of the pro-myelo-monocytic U937 cells to synovial transplants, even more efficiently than TNF-alpha, but without modifications of CAMs' expression.
Ingegnoli
F
F
Cattedra di Reumatologia, Università degli Studi di Milano, Istituto Ortopedico G. Pini, Italia.
Blades
M
M
Manzo
A
A
Wahid
S
S
Perretti
M
M
Panayi
G
G
Pitzalis
C
C
D000818:Animals; D001172:Arthritis, Rheumatoid / Q000209:etiology* / Q000473:pathology; D015815:Cell Adhesion Molecules / Q000096:biosynthesis / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002609:Chediak-Higashi Syndrome / Q000235:genetics; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000494:pharmacology*; D002630:Chemotactic Factors / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D005856:Germ-Free Life; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008214:Lymphocytes / Q000473:pathology; D008264:Macrophages / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D016513:Mice, SCID; D011506:Proteins / Q000235:genetics / Q000502:physiology; D013583:Synovial Membrane / Q000378:metabolism / Q000473:pathology* / Q000637:transplantation; D014183:Transplantation, Heterologous; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D020298:U937 Cells / Q000166:cytology / Q000187:drug effects; D033921:Vesicular Transport Proteins
C515255:CXCL12 protein, human; D015815:Cell Adhesion Molecules; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D002630:Chemotactic Factors; C515256:Cxcl12 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; C102161:LYST protein, human; C491133:Lyst protein, mouse; D011506:Proteins; D014409:Tumor Necrosis Factor-alpha; D033921:Vesicular Transport Proteins