ULTRASTRUCTURAL ANALYSIS OF HUMAN SKIN BIOPSY SPECIMENS FROM PATIENTSRECEIVING RECOMBINANT HUMAN STEM-CELL FACTOR - SUBCUTANEOUS INJECTIONOF RHSCF INDUCES DERMAL MAST-CELL DEGRANULATION AND GRANULOCYTE RECRUITMENT AT THE INJECTION SITE

We performed an ultrastructural analysis of 10 skin biopsy specimens t hat had been obtained from three women who were undergoing daily subcu taneous dosing with recombinant methionyl-human stem cell factor (rhSC F) as part of a phase I clinical trial. The biopsy specimens were obta ined at sites of subcutaneous administration of rhSCF, within approxim ately 1 to 2 hours of rhSCF injection, and, at the same time, at contr alateral control sites that had not been directly injected with rhSCF, We previously reported that subcutaneous dosing with rhSCF in these s ubjects induced the local development of a wheal and flare response, w hich was associated with evidence of mast cell degranulation, as well as a systemic increase in numbers of cutaneous mast cells, The present electron microscopic analysis revealed that all biopsies of swollen, erythematous rhSCF-injected sites exhibited anaphylactic degranulation of both mature and immature mast cells, an acute inflammatory respons e characterized by the migration of neutrophils, basophils (some of wh ich exhibited evidence of piecemeal degranulation), and eosinophils th rough blood vessel walls into the perivascular and extravascular space s, and edema and fibrin deposition within the interstitium. By contras t, the control biopsies contained no evidence of mast cell degranulati on or acute inflammation, However, both control and rhSCF-injected sit es exhibited mast cells that were undergoing granule building and matu ration. Thus at the doses tested in these subjects, subcutaneous injec tion of rhSCF induced anaphylactic-type degranulation of dermal mast c ells at the injection site, with an acute inflammatory response that w as associated with the recruitment of granulocytes. By contrast, mast cells at sites distant from those directly injected with rhSCF exhibit ed no evidence of enhanced secretion.