CUTANEOUS MAST-CELL DEGRANULATION IN RATS RECEIVING INJECTIONS OF RECOMBINANT HUMAN INTERLEUKIN-1 RECEPTOR ANTAGONIST (RHIL-1RA) AND OR ITSVEHICLE - POSSIBLE CLINICAL IMPLICATIONS/
A. Bendele et al., CUTANEOUS MAST-CELL DEGRANULATION IN RATS RECEIVING INJECTIONS OF RECOMBINANT HUMAN INTERLEUKIN-1 RECEPTOR ANTAGONIST (RHIL-1RA) AND OR ITSVEHICLE - POSSIBLE CLINICAL IMPLICATIONS/, The Journal of laboratory and clinical medicine, 125(4), 1995, pp. 493-500
Citations number
18
Categorie Soggetti
Medical Laboratory Technology","Medicine, General & Internal
Human recombinant interleukin-1 receptor antagonist (rhIL-1ra), a 17.2
kd protein, is currently in clinical trials for the treatment of rheu
matoid arthritis (RA). Skin reactions in some patients with RA prompte
d investigation of a possible pathogenesis involving nonimmunologicall
y mediated mast cell degranulation. Rats injected intradermally with 2
0 mu l 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 eliminat
ed by subcutaneous or local treatment with the antihistamine diphenhyd
ramine. Histologic evaluation of skin sections from rats injected intr
adermally with CSEP or rhIL-1ra in CSEP revealed mast cell degranulati
on and edema, features not seen in sites injected with PBS or BSA in P
BS. Components of the vehicle were investigated individually for their
capacity to cause the reaction. Na-citrate (10 mmol/L) induced a grea
ter 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. Evens blue dye permeabili
ty 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. The addition of 100 mu g of diphenhydramine to rhIL-1ra in
CSEP completely inhibited the permeability increases, and the additio
n of 30 mu g resulted in ct reaction that was similar to that of the P
BS control. Skin reactions in animals injected with rhIL-1ra in PBS we
re reduced (56%) as compared with those occurring in rats injected wit
h rhIL-1ra in CSEP. These results indicate that intradermal or subcuta
neous injection of CSEP (rhIL-1ra vehicle) or high concentrations of r
hIL-1ra in CSEP or PBS induces nonimmunologically mediated cutaneous m
ast cell degranulation in rats. A pseudoallergic response to CSEP vehi
cle in combination with rhIL-1ra may be contributory to the pathogenes
is of skin reactions in patients with RA treated with high concentrati
ons of this protein.