title: In vitro cytotoxicity as a marker of hypersensitivity to sulphamethoxazole in patients with HIV.
abstract: Hypersensitivity to trimethoprim-sulphamethoxazole (TMP-SMX) in patients with HIV infection may be a result of either immune dysregulation, a direct cytotoxicity of the SMX-hydroxylamine metabolite (SMX-HA) (rather than SMX per se), or glutathione deficiency. We evaluated the in vitro cytotoxicity of SMX and SMX-HA to peripheral blood mononuclear cells (PBMC) of HIV-infected subjects to determine if the degree of in vitro cytotoxicity is associated with hypersensitivity, whether glutathione inhibits cytotoxicity, and whether in vitro cytotoxicity is predictive for the development of hypersensitivity. Given that fever is often a prominent feature of hypersensitivity, we also assessed whether SMX or SMX-HA could induce the in vitro production of IL-1 beta, IL-6 or tumour necrosis factor-alpha (TNF-alpha) by PBMC. The cytotoxicities of SMX and SMX-HA to PBMC were assessed in 45 HIV-infected patients with prior TMP-SMX therapy, and in eight HIV- controls. Twelve HIV-infected subjects were studied prospectively before primary Pneumocystis carinii pneumonia (PCP) therapy or rechallenge with TMP-SMX in previously hypersensitive subjects. Cytokine production was measured in four hypersensitive and two non-hypersensitive HIV-infected subjects, and three HIV-uninfected controls. The cytotoxicity of SMX-HA to PBMC was significantly greater in the 22 HIV-infected patients with prior hypersensitivity than both the 23 HIV-infected patients without hypersensitivity and the control group. Cytotoxicity was significantly reduced by glutathione only in the hypersensitive group. SMX did not induce cytotoxicity in any group. In 12 subjects studied prospectively, SMX-HA cytotoxicity was also significantly greater in those with subsequent hypersensitivity. Exposure of PBMC to SMX-HA resulted in a modest increase in the production of IL-6, IL-1 beta and TNF-alpha, although no major difference was detected between subjects with or without hypersensitivity. These data suggest that SMX-HA and glutathione deficiency are involved in the pathogenesis of hypersensitivity to TMP-SMX in HIV-infected patients, and that in vitro cytotoxicity could be useful in the diagnosis of hypersensitivity and predicting its likelihood.
authors.affiliation: Centre for Immunology, St. Vincent's Hospital, Sydney, Australia.
authors.forename: A
authors.initials: A
authors.lastname: Carr
authors.forename: B
authors.initials: B
authors.lastname: Tindall
authors.forename: R
authors.initials: R
authors.lastname: Penny
authors.forename: D A
authors.initials: DA
authors.lastname: Cooper
mesh_terms: D000328:Adult; D016516:CD4-CD8 Ratio; D016207:Cytokines / Q000096:biosynthesis; D003602:Cytotoxicity, Immunologic; D004342:Drug Hypersensitivity / Q000209:etiology*; D005978:Glutathione / Q000502:physiology; D015658:HIV Infections / Q000276:immunology*; D006801:Humans; D008297:Male; D013420:Sulfamethoxazole / Q000009:adverse effects / Q000031:analogs & derivatives / Q000276:immunology* / Q000378:metabolism; D015662:Trimethoprim, Sulfamethoxazole Drug Combination / Q000276:immunology
chemical_list: D016207:Cytokines; C059873:sulfamethoxazole hydroxylamine; D015662:Trimethoprim, Sulfamethoxazole Drug Combination; D005978:Glutathione; D013420:Sulfamethoxazole