THE EXPRESSION OF CYTOKINES, GROWTH-FACTORS AND ICAM-1 IN THE HEALINGOF HUMAN CUTANEOUS XENOGRAFTS ON NUDE-MICE

We postulate that wound healing is an orderly process mediated by a pr ogrammed expression of cytokines and growth factors. We suggest that t hese factors are produced in a consistent sequence, in regulated quant ities and eliminated when their function is complete. We report here t he results of studies on several cytokines, growth factors and the int ercellular adhesion molecule expressed during the healing of human ski n grafted onto athymic nude mice. Signs of healing of grafts were visi ble clinically around 3-5 days post-graft and were completed by 4 week s post-graft. During the Ist 2 weeks, we observed the following. (i) K -14 keratin was prominent throughout the entire epidermis. Thereafter it was limited to basal cell layers. (ii) Langerhans cells were not de tectable with anti-human CD1a antibodies during the first week of heal ing but were clearly detectable 2 weeks post-graft. (iii) DOPA (dihydr oxy phenylalanine) positive melanocytes gradually increased with time. The epidermis 21 to 28 days post-graft clinically and histologically seemed to be morphologically intact. Interleukin-l (IL-1) was clearly detected in some basal cells of the epidermis, especially in melanocyt es and some keratinocytes during the early stage of healing. Transform ing growth factor-alpha (TGF-alpha) was detected in epidermis first in melanocytes and some keratinocytes shortly after grafting and again i n the late stage of healing. It was also found in some dermal cells. I ts expression coincided with keratinocyte proliferation and melanocyte migration. TGF-D was strongly expressed in the epidermis and dermis a fter the first week post graft. (iv) ICAM-1 was transiently expressed only at the onset of healing. We previously reported that pro-opiomela nocortin and its derivatives MSH/ACTH are expressed strongly during th e healing of human xenografts. The 4 additional molecules which are th e subject of this report all are expressed in healing human skin in a predictable sequence and quantity (intensity of stain). Together these data support our hypothesis that healing is a highly regulated proces s mediated by numerous cytokines.