RESUMO
We report here identification of novel mimicry epitopes for interphotoreceptor retinoid-binding protein (IRBP) 201-216, a candidate ocular antigen that causes experimental autoimmune uveoretinitis (EAU) in A/J mice. One mimicry epitope from Ehrlichia canis (EHC), designated EHC 44-59, induced cross-reactive T cells for IRBP 201-216 capable of producing T helper (Th)1 and Th17 cytokines, but failed to induce EAU in A/J mice. In addition, animals first primed with suboptimal doses of IRBP 201-216 and subsequently immunized with EHC 44-59 did not develop EAU; rather, the mimicry epitope prevented the disease induced by IRBP 201-216. However, alteration in the composition of EHC 44-59 by substituting alanine with valine at position 49, similar to the composition of IRBP 201-216, enabled the mimicry epitope to acquire uveitogenicity. The data provide new insights as to how microbes containing mimicry sequences for retinal antigens can prevent ocular inflammation by acting as naturally occurring altered peptide ligands.
Assuntos
Doenças Autoimunes do Sistema Nervoso/prevenção & controle , Ehrlichia canis/imunologia , Ehrlichiose/prevenção & controle , Mimetismo Molecular/imunologia , Retinite/prevenção & controle , Uveíte/prevenção & controle , Sequência de Aminoácidos , Animais , Doenças Autoimunes do Sistema Nervoso/imunologia , Doenças Autoimunes do Sistema Nervoso/microbiologia , Bovinos , Ehrlichia canis/genética , Ehrlichiose/imunologia , Ehrlichiose/microbiologia , Proteínas do Olho/administração & dosagem , Proteínas do Olho/genética , Proteínas do Olho/metabolismo , Feminino , Ligantes , Camundongos , Camundongos Endogâmicos A , Dados de Sequência Molecular , Retinite/imunologia , Retinite/microbiologia , Proteínas de Ligação ao Retinol/administração & dosagem , Proteínas de Ligação ao Retinol/genética , Proteínas de Ligação ao Retinol/metabolismo , Uveíte/imunologia , Uveíte/microbiologiaRESUMO
PURPOSE: The authors compare the intravitreal efficacy of ciprofloxacin, vancomycin and imipenem, in treating experimental Bacillus cereus endophthalmitis. METHODS: Thirty-three Yorkshire pigs received a surgically induced injury to the right eye, which was then repaired and injected with 8400 colony forming units of live B. cereus. Nine pigs received no therapy and served as a natural history group. Twenty-four other pigs then were randomized into a treatment group with ciprofloxacin (n = 6), vancomycin (n = 6), imipenem (n = 6), or normal saline (n = 6). Eyes were examined clinically 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours after inoculation. After 24 hours, the eyes were enucleated for histologic study. RESULTS: Experimental disease was characterized by an aggressively developing endophthalmitis, with retinitis and vitritis developing at 4 hours. Histologic examination showed vitreous abscess and retinal necrosis. Both vancomycin- and imipenem-treated group had less inflammation and tissue destruction than control animals, based on the Wilcoxon rank sum test (P < 0.05). Ciprofloxacin-treated animals showed significantly more intraocular destruction and were indistinguishable from controls. CONCLUSION: Vancomycin and imipenem appear to limit inflammation and tissue destruction when given early in the course of experimental posttraumatic endophthalmitis caused by B. cereus. Results with ciprofloxacin are less conclusive and warrant further investigation.
Assuntos
Antibacterianos/uso terapêutico , Infecções por Bacillaceae/tratamento farmacológico , Bacillus cereus/isolamento & purificação , Endoftalmite/tratamento farmacológico , Infecções Oculares Bacterianas/tratamento farmacológico , Ferimentos Oculares Penetrantes/tratamento farmacológico , Animais , Anti-Infecciosos/uso terapêutico , Infecções por Bacillaceae/etiologia , Infecções por Bacillaceae/patologia , Ciprofloxacina/uso terapêutico , Modelos Animais de Doenças , Endoftalmite/microbiologia , Endoftalmite/patologia , Oftalmopatias/tratamento farmacológico , Oftalmopatias/etiologia , Oftalmopatias/microbiologia , Infecções Oculares Bacterianas/etiologia , Infecções Oculares Bacterianas/patologia , Ferimentos Oculares Penetrantes/microbiologia , Ferimentos Oculares Penetrantes/patologia , Imipenem/uso terapêutico , Projetos Piloto , Distribuição Aleatória , Retinite/tratamento farmacológico , Retinite/etiologia , Retinite/microbiologia , Suínos , Tienamicinas/uso terapêutico , Vancomicina/uso terapêutico , Corpo Vítreo/efeitos dos fármacos , Corpo Vítreo/microbiologia , Corpo Vítreo/patologiaRESUMO
PURPOSE: To determine the incidence, pathophysiology, clinical outcome, and survival in patients with clinically resistant retinitis. METHODS: Cytomegalovirus (CMV) retinitis was prospectively studied in 100 patients with acquired immune deficiency syndrome (AIDS). In 11 of these patients, clinically resistant retinitis developed, defined as new activity or progression, despite at least 8 consecutive weeks of induction doses of either foscarnet or ganciclovir. Fundus photography, pharmacokinetics, CMV cultures and sensitivities, and survival analyses were studied. The therapeutic interventions attempted after clinically resistant retinitis was identified included continuing a high dose (induction level) of the same antiviral drug, changing the antiviral drug, and combining antiviral therapy with foscarnet and ganciclovir. RESULTS: Clinically resistant retinitis occurred in 11 (11%) of 100 patients with CMV retinitis and appeared to be a manifestation of acquired CMV antiviral drug resistance. Drug metabolism and pharmacokinetics in these patients were normal. The use of combination therapy with foscarnet and ganciclovir was effective in halting the progression of retinitis in three (75%) of four patients (6 of 7 eyes able to be evaluated) receiving combination therapy. CONCLUSION: Clinically resistant retinitis is a manifestation of infection by CMV that has acquired drug resistance. In these patients, combination antiviral drug treatment should be considered. It is likely that clinically resistant retinitis will become more frequent as patients with CMV retinitis and AIDS survive longer.
Assuntos
Infecções Oportunistas Relacionadas com a AIDS/tratamento farmacológico , Infecções por Citomegalovirus/tratamento farmacológico , Infecções Oculares Virais/tratamento farmacológico , Ganciclovir/uso terapêutico , Retinite/tratamento farmacológico , Infecções Oportunistas Relacionadas com a AIDS/fisiopatologia , Adulto , Citomegalovirus/efeitos dos fármacos , Infecções por Citomegalovirus/fisiopatologia , Resistência Microbiana a Medicamentos , Quimioterapia Combinada , Infecções Oculares Virais/fisiopatologia , Feminino , Foscarnet/farmacocinética , Foscarnet/uso terapêutico , Fundo de Olho , Ganciclovir/farmacocinética , Humanos , Masculino , Testes de Sensibilidade Microbiana , Estudos Prospectivos , Retinite/microbiologia , Retinite/fisiopatologia , Taxa de Sobrevida , Acuidade VisualAssuntos
Síndrome da Imunodeficiência Adquirida , Antivirais/uso terapêutico , Infecções por Citomegalovirus/tratamento farmacológico , Infecções Oculares Virais/tratamento farmacológico , Rotulagem de Alimentos/legislação & jurisprudência , Hidrocortisona/provisão & distribuição , Ácido Fosfonoacéticos/análogos & derivados , Retinite/tratamento farmacológico , Foscarnet , Humanos , Medicamentos sem Prescrição/provisão & distribuição , Ácido Fosfonoacéticos/uso terapêutico , Retinite/microbiologia , Estados Unidos , United States Food and Drug AdministrationRESUMO
A genetically engineered herpes simplex virus type 1 (HSV-1, strain RH116) that expresses beta-galactosidase (beta-gal) was used as a marker to trace the route of interocular spread of HSV-1 after anterior chamber (AC) inoculation into BALB/c mice. Because RH116 is thymidine kinase deficient (TK-), the wild-type TK+ KOS strain of HSV-1 was used as a helper virus to complement RH116 during in vivo infection. After coinfection of BALB/c mice with RH116 and KOS in the AC of one eye, beta-gal expression by RH116 was detected in both the eyes and in the central nervous system (CNS). Our results suggest that after AC inoculation into BALB/c mice: (1) virus spreads from the injected eye to the CNS through parasympathetic fibers of the oculomotor nerve that supply the iris and ciliary body; (2) virus spread in the CNS is limited primarily to nuclei of the visual system and the suprachiasmatic area of the hypothalamus; and (3) virus is transmitted from the CNS to the retina of the contralateral eye by retrograde axonal transport through the optic nerve along the endocrine-optic pathway between the retina and the suprachiasmatic nucleus of the hypothalamus.
Assuntos
Câmara Anterior/microbiologia , Sistema Nervoso Central/microbiologia , Simplexvirus/fisiologia , Animais , Sistema Nervoso Central/enzimologia , Olho/enzimologia , Feminino , Hipotálamo/enzimologia , Injeções , Camundongos , Camundongos Endogâmicos BALB C , Nervo Óptico/enzimologia , Retinite/microbiologia , Simplexvirus/isolamento & purificação , Coloração e Rotulagem , Fatores de Tempo , Distribuição Tecidual , beta-Galactosidase/metabolismoRESUMO
Ten patients with acquired immunodeficiency syndrome with newly diagnosed cytomegalovirus (CMV) retinitis were treated with an induction regimen of intravenous foscarnet, 60 mg/kg of body weight, administered as a 2-h infusion and repeated every 8 h for 14 days. At the end of induction, 9 of 10 patients had stabilized (no new retinal lesions and stable old lesions [7 patients]) or improved (decreased retinal opacification [2 patients]). All eight patients with CMV in urine or blood upon entry into the study had negative urine and blood cultures at the end of induction. After induction therapy, seven patients continued maintenance foscarnet therapy, 60 mg/kg as a single daily infusion, 5 days/week. In six patients, retinal lesions increased in size after 2 to 32 weeks of maintenance therapy. One was invaluable because a retinal detachment developed. Only 9 of 42 blood and urine cultures obtained during maintenance foscarnet therapy yielded CMV, compared with 7 of 14 obtained prior to the initiation of foscarnet induction therapy (P = 0.04). Foscarnet toxicity was mild and infrequent: elevation in serum creatinine by 0.5 to 1.3 mg/dl over the base line (two patients), muscle twitching (three patients), hemoglobin decrease by 1 mg/dl (two patients), nausea (two patients), absolute neutrophil count decrease by 50% (one patient), rise in serum phosphorus to greater than 5.5 mg/dl (four patients), and proteinuria (two patients). Intermittently administered intravenous foscarnet appears to be an effective, relatively nontoxic therapy for CMV retinitis. Additional studies to determine the optimal dosage for maintenance therapy are needed, as are comparative trials with ganciclovir.