Cutaneous mast cell degranulation in rats receiving injections of recombinant human interleukin-1 receptor antagonist (rhIL-1ra) and/or its vehicle: possible clinical implications.
Human recombinant interleukin-1 receptor antagonist (rhIL-1ra), a 17.2 kd protein is currently in clinical trials for the treatment of rheumatoid arthritis (RA). Skin reactions in some patients with RA prompted investigation of a possible pathogenesis involving nonimmunologically mediated mast cell degranulation. Rats injected intradermally with 20 microliters of rhIL-1ra (100 or 200 mg/ml) or the rhIL-1ra vehicle CSEP (10 mmol/L Na-citrate, 0.5 mmol/L ethylenediaminetetraacetic acid (EDTA), 0.1% polysorbate 80, 140 mmol/L NaCl, pH 6.5) had marked (15x or 10x, respectively) Evans blue dye permeability increases as compared with rats injected with phosphate-buffered saline solution (PBS) or bovine serum albumin (BSA). The permeability changes were reduced or eliminated by subcutaneous or local treatment with the antihistamine diphenhydramine. Histologic evaluation of skin sections from rats injected intradermally with CSEP or rhIL-1ra in CSEP revealed mast cell degranulation and edema, features not seen in sites injected with PBS or BSA in PBS. Components of the vehicle were investigated individually for their capacity to cause the reaction. Na-citrate (10 mmol/L) induced a greater increase in permeability than did EDTA (0.5 mmol/L) or polysorbate 80 (0.1%), and all produced reactions that were significantly greater than those occurring at PBS-injected sites. Evans blue dye permeability increases after subcutaneous injection of 1 ml of rhIL-1ra (100 mg/ml) in CSEP (with and without diphenhydramine) or rhIL-1ra in PBS were evaluated.(ABSTRACT TRUNCATED AT 250 WORDS)
Bendele
A
A
Synergen, Boulder, CO 80301-2546, USA.
Colloton
M
M
Vrkljan
M
M
Morris
J
J
Sabados
K
K
D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects; D015550:Cell Degranulation / Q000187:drug effects*; D004155:Diphenhydramine / Q000494:pharmacology; D005070:Evans Blue / Q000493:pharmacokinetics; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein; D008297:Male; D008407:Mast Cells / Q000187:drug effects* / Q000502:physiology; D014677:Pharmaceutical Vehicles; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors*; D011994:Recombinant Proteins / Q000494:pharmacology; D012795:Sialoglycoproteins / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D012867:Skin / Q000187:drug effects
C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D014677:Pharmaceutical Vehicles; D017472:Receptors, Interleukin-1; D011994:Recombinant Proteins; D012795:Sialoglycoproteins; D005070:Evans Blue; D004155:Diphenhydramine