Chemokine-induced cutaneous inflammatory cell infiltration in a model of Hu-PBMC-SCID mice grafted with human skin.
Recently, certain chemokines and chemokine receptors have been preferentially associated with the selective recruitment in vitro of type 1 T cells, such as IP-10 and its receptor CXCR3, or type 2 T cells such as monocyte-derived chemokine (MDC) and eotaxin and their receptors CCR4 and CCR3. Very few models have provided confirmation of these findings in vivo. Taking advantage of the humanized SCID mouse model grafted with autologous human skin, the ability of the chemokines IP-10, MDC, eotaxin, and RANTES to stimulate cell recruitment was investigated. Intradermal IP-10 injection resulted in an influx of CD4+ T lymphocytes but also surprisingly in the recruitment of dendritic cells. MDC recruited mainly CD8+ T lymphocytes, and had little effect on eosinophils. As predicted, eotaxin was a potent inducer of eosinophil and basophil migration, also recruiting CD4+ T cells. RANTES, a ubiquitous chemokine associated with both type 1 and type 2 profiles, was able to recruit all cell types. CXCR3-positive cells were preferentially recruited by IP-10, whereas CCR3- and CCR4-positive cells were predominantly found after injection of eotaxin and MDC. Thus, in a human environment in vivo, some chemokines have the ability to recruit cells expressing chemokine receptors preferentially expressed on type 1 or type 2 cells. Further investigations revealed that MDC and eotaxin induced the recruitment of type 2, but not type 1, cytokine-producing cells. RANTES, on the other hand, induced the migration of both type 1 and type 2 cytokine-secreting cells, whereas IP-10 did not induce the recruitment of either subtype. These studies provide detailed information on the properties of MDC, eotaxin, IP-10, and RANTES as chemotactic molecules in skin in vivo. The use of the humanized SCID mouse model grafted with human skin is validated as a useful model for the evaluation of chemokine function in the inflammatory reaction, and suggests that therapeutic targeting of certain chemokines might be of interest in diseases associated preferentially with a type 1 or type 2 profile.
INSERM U-416, Institut Pasteur de Lille, 1 rue du Prof. Calmette, B.P. 245, 59 019 Lille, France.
O
O
Fahy
H
H
Porte
S
S
Sénéchal
H
H
Vorng
A R
AR
McEuen
M G
MG
Buckley
A F
AF
Walls
B
B
Wallaert
A B
AB
Tonnel
A
A
Tsicopoulos
D000818:Animals; D001491:Basophils / Q000276:immunology; D018925:Chemokines / Q000494:pharmacology*; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000276:immunology; D004195:Disease Models, Animal; D004804:Eosinophils / Q000276:immunology; D006801:Humans; D007249:Inflammation / Q000276:immunology*; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000637:transplantation; D008213:Lymphocyte Activation; D008264:Macrophages / Q000276:immunology; D051379:Mice; D016513:Mice, SCID; D019707:Receptors, Chemokine / Q000032:analysis; D012867:Skin / Q000276:immunology; D016038:Skin Transplantation; D016176:T-Lymphocyte Subsets / Q000145:classification; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D014184:Transplantation, Homologous
D018925:Chemokines; D016207:Cytokines; D019707:Receptors, Chemokine