Ultrastructural analysis of human skin biopsy specimens from patients receiving recombinant human stem cell factor: subcutaneous injection of rhSCF induces dermal mast cell degranulation and granulocyte recruitment at the injection site.
We performed an ultrastructural analysis of 10 skin biopsy specimens that had been obtained from three women who were undergoing daily subcutaneous dosing with recombinant methionyl-human stem cell factor (rhSCF) as part of a phase I clinical trial. The biopsy specimens were obtained at sites of subcutaneous administration of rhSCF, within approximately 1 to 2 hours of rhSCF injection, and, at the same time, at contralateral control sites that had not been directly injected with rhSCF. We previously reported that subcutaneous dosing with rhSCF in these subjects induced the local development of a wheal and flare response, which 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 response characterized by the migration of neutrophils, basophils (some of which exhibited evidence of piecemeal degranulation), and eosinophils through blood vessel walls into the perivascular and extravascular spaces, and edema and fibrin deposition within the interstitium. By contrast, the control biopsies contained no evidence of mast cell degranulation or acute inflammation. However, both control and rhSCF-injected sites exhibited mast cells that were undergoing granule building and maturation. Thus at the doses tested in these subjects, subcutaneous injection of rhSCF induced anaphylactic-type degranulation of dermal mast cells at the injection site, with an acute inflammatory response that was associated with the recruitment of granulocytes. By contrast, mast cells at sites distant from those directly injected with rhSCF exhibited no evidence of enhanced secretion.
Dvorak
A M
AM
Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Mass 02215, USA.
Costa
J J
JJ
Monahan-Earley
R A
RA
Fox
P
P
Galli
S J
SJ
D000707:Anaphylaxis / Q000139:chemically induced* / Q000276:immunology* / Q000473:pathology*; D001706:Biopsy; D015550:Cell Degranulation / Q000187:drug effects; D005260:Female; D006098:Granulocytes / Q000276:immunology* / Q000473:pathology* / Q000648:ultrastructure; D006801:Humans; D008407:Mast Cells / Q000276:immunology* / Q000473:pathology* / Q000648:ultrastructure; D008854:Microscopy, Electron; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects; D012867:Skin / Q000187:drug effects / Q000276:immunology* / Q000473:pathology* / Q000648:ultrastructure; D019089:Stem Cell Factor / Q000008:administration & dosage* / Q000009:adverse effects*
D011994:Recombinant Proteins; D019089:Stem Cell Factor