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 preferential ly associated with the selective recruitment in vitro of type 1 T cells, su ch as IP-10 and its receptor CXCR3, or type 2 T cells such as monocyte-deri ved chemokine (MDC) and eotaxin and their receptors CCR4 and CCR3, Very few models have provided confirmation of these findings in vivo. Taking advant age of the humanized SCID mouse model grafted with autologous human skin, t he ability of the chemokines IP-10, MDC, eotaxin, and RANTES to stimulate c ell recruitment was investigated. Intradermal IP-10 injection resulted in a n influx of CD4(+) T lymphocytes but also surprisingly in the recruitment o f dendritic cells, MDC recruited mainly CD8(+) T lymphocytes, and had Littl e effect on eosinophils. As predicted, eotaxin was a potent inducer of eosi nophil and basophil migration, also recruiting CD4(+) T cells. RANTES, a ub iquitous chemokine associated with both type 1 and type 2 profiles, was abl e to recruit all cell types. CXCR3-positive cells were preferentially recru ited by IP-10, whereas CCR3- and CCR4-positive cells were predominantly fou nd after injection of eotaxin and MDC. Thus, in a human environment in vivo , some chemokines have the ability to recruit cells expressing chemokine re ceptors preferentially expressed on type 1 or type 2 cells. Further investi gations revealed that MDC and eotaxin induced the recruitment of type 2, bu t 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 I P-10 did not induce the recruitment of either subtype, These studies provid e 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 mo use model grafted with human skin is validated as a useful model for the ev aluation of chemokine function in the inflammatory reaction, and suggests t hat therapeutic targeting of certain chemokines might be of interest in dis eases associated preferentially with a type 1 or type 2 profile.