In vivo efficacy of the selective H4 antagonist JNJ 7777120 in a sephadex model of pulmonary eosinophilia

Garry Douglas, Chris Brown and Wai Liu. Allergy & Respiratory Biology, Pfizer Global R&D, Sandwich, UK.

The histamine H4 receptor is selectively expressed on immune cells such as T-cells, neutrophils, eosinophils, and mast cells. The H4 receptor mediates histamine-induced chemotaxis of eosinophils in vitro and mast cells both in vitro and in vivo (Fung-Leung et al., 2004). The selective H4 receptor antagonist JNJ 7777120 has recently been described to possess anti-inflammatory activity in a mouse model of zymosan-induced peritonitis characterised by a neutrophil influx (Thurmond et al., 2004). Here we describe the anti-inflammatory effects of this compound in a rat model of Sephadex-induced pulmonary eosinophilia, a model of lung inflammation associated with a Th2-type T-cell mediated response (Haddad et al., 2002).

Male Sprague-Dawley rats (350-400 g; n=6 per group) were pre-treated subcutaneously with vehicle (acidified PBS; pH 5.5; 1.0 ml kg-1) or JNJ 7777120 (3-30 mg kg-1) 15 minutes before intratracheal administration of Sephadex G-200 superfine (5 mg kg-1) suspended in sterile saline. Rats were euthanised (intraperitoneal pentobarbitone sodium; 200 mg kg-1) and bronchoalveolar lavage (BAL) was performed by sequential instillation and aspiration of four 2.5 ml aliquots of PBS (pH 7.4, containing 2.6 mM EDTA) 24-hours after Sephadex instillation. The total number of leukocytes in the BAL sample was counted using an automated haematology analyser (Beckman Coulter AcTDiff) and eosinophil numbers were enumerated by differential leukocyte counts obtained from cytocentrifuge preparations using standard morphological criteria under light microscopy.

JNJ 7777120 produced a dose-related inhibition of eosinophil migration into rat airways as assessed by BAL with an approximate ID50 of 10 mg kg-1 (Table 1).

Table 1.

* P<0.01 versus vehicle pre-treated group (ANOVA).

These data support a role of the histamine H4 receptor in eosinophil homing and tissue recruitment using an animal model of lung inflammation. The selective histamine H 4 receptor antagonist JNJ 7777120 has demonstrated suppression of eosinophil recruitment in a model that has been demonstrated to be T-cell dependent.

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Haddad, E-B et al. (2002) J.Immunol., 168 : 3004-3016.
Thurmond, L et al. (2004) J.Pharmacol. Exp. Ther., 309 : 404-413.