Pharmacologic manipulation of a four day murine delayed type hypersensitivity model

Abstract

A murine delayed-type hypersensitivity (DTH) model was developed as a tool for drug discovery. Time course studies indicated that hind paw swelling was maximal at four days post-sensitization with picryl chloride. A pharmacological survey involving daily administration of drugs revealed that as a class, the glucocorticoids (e.g. dexamethasone and corticosterone) were the most potent inhibitors of the DTH response. The immunosuppressants, methotrexate, cyclosporine A, cyclophosphamide, and azathioprine, were all able to suppress the DTH response, with methotrexate being the most potent suppressor of paw swelling. Likewise, non-steroidal anti-inflammatory agents (e.g. indomethacin, piroxicam, diclofenac, and naproxen) all suppressed the DTH response, with indomethacin and piroxicam being the most potent suppressors. A series of central nervous system affecting drugs, including serotonin agonists [e.g. trifluromethylphenylpiperazine (tfMPP), 1-(3-chlorophenyl)piperazine (mCPP), quipazine, and 8-hydroxy-DPAT hydrobromide (8-OH DPAT)], and serotonin antagonists (e.g. cyproheptadiene, ketanserin, and mianserin) were examined in the 4 day DTH model. Except for 8-OH DPAT, all of the serotonin agonists were able to suppress the DTH response, with mCPP being the most potent suppressor. In contrast, none of the tested serotonin antagonists had any effect on the DTH response. The histamine antagonists (e.g. cimetidine and chlorphineramine) were largely ineffective in suppressing the DTH response. These data provide a pharmacological profile for a series of immunomodulator, non-steroidal anti-inflammatory, and central nervous system active compounds in a classic immunologic model.

The specificity of JAK3 kinase inhibitors

“…As previously described, delayed-type hypersensitivity (DTH) swelling responses have been used to follow the activity of immunosuppressive molecules in vivo, 6 including CP-690550. 7 It is an in vivo T cell-dependent immune response manifested as an inflammatory reaction that peaks in intensity 24 to 48 hours after antigen challenge in previously sensitized animals.…”

The Novel JAK-3 Inhibitor CP-690550 Is a Potent Immunosuppressive Agent in Various Murine Models

“…Delayed‐type hypersensitivity has been used to evaluate compounds that modify T‐cell function (9,10). For example, rapamycin dose‐dependently inhibited SRBC‐induced footpad swelling with a maximum response (85%) following daily dosing of 10 mg/kg, i.p.…”