Following activation within secondary lymphoid tissue, CD8 T cells must migrate to targets, such as infected self tissue, allografts, and tumors, to mediate contact-dependent effector functions. To test whether the pattern of migration of activated CD8 T cells was dependent on the site of Ag encounter, we examined the distribution of mouse Ag-specific CD8 T cells following local challenges. Our findings indicated that activated CD8 T cells migrated pervasively to all nonlymphoid organs irrespective of the site of initial Ag engagement. Using an adoptive transfer system, migration of nonlymphoid memory cells was also examined. Although some limited preference for the tissue of origin was noted, transferred CD8 memory T cells from various nonlymphoid tissues migrated promiscuously, except to the intestinal mucosa, supporting the concept that distinct memory pools may exist. However, regardless of the tissue of origin, reactivation of transferred memory cells resulted in widespread dissemination of new effector cells. These data indicated that recently activated primary or memory CD8 T cells were transiently endowed with the ability to traffic to all nonlymphoid organs, while memory cell trafficking was more restricted. These observations will help refine our understanding of effector and memory CD8 T cell migration patterns.
The etiology and pathogenesis of bile duct obstruction in children with biliary atresia are largely unknown. We have previously reported that, despite phenotypic heterogeneity, genomic signatures of livers from patients display a proinflammatory phenotype. Here, we address the hypothesis that production of IFN-γ is a key pathogenic mechanism of disease using a mouse model of rotavirus-induced biliary atresia. We found that rotavirus infection of neonatal mice has a unique tropism to bile duct cells, and it triggers a hepatobiliary inflammation by IFN-γ-producing CD4 + and CD8 + lymphocytes. The inflammation is tissue specific, resulting in progressive jaundice, growth failure, and greater than 90% mortality due to obstruction of extrahepatic bile ducts. In this model, the genetic loss of IFN-γ did not alter the onset of jaundice, but it remarkably suppressed the tissue-specific targeting of T lymphocytes and completely prevented the inflammatory and fibrosing obstruction of extrahepatic bile ducts. As a consequence, jaundice resolved, and long-term survival improved to greater than 80%. Notably, administration of recombinant IFN-γ led to recurrence of bile duct obstruction following rotavirus infection of IFN-γ-deficient mice. Thus, IFN-γ-driven obstruction of bile ducts is a key pathogenic mechanism of disease and may constitute a therapeutic target to block disease progression in patients with biliary atresia.
An unpassaged, safety-tested strain (CJN) of human rotavirus from a stool specimen of a hospitalized child was administered orally to 62 adult volunteers for determination of the dose required to produce infection with or without illness. Subjects ingested doses ranging from 9 X 10(-3) to 9 X 10(4) focus-forming units in buffered salt solution after consumption of 50 ml of 4% NaHCO3. The amount of virus in the inoculum required to cause infection (shedding of virus, seroconversion, or both) in study subjects was comparable to the minimum detectable in cultures of primary monkey kidney cells. Seventeen of 30 infected subjects became ill with doses equivalent to that required for infection. Although the preinoculation titers of serum neutralizing antibody to the challenge virus in study subjects ranged from less than 1:2 to 1:1,600, the concentration of serum antibody could not be correlated with protection from infection or illness in subjects given an infectious dose of virus.
Chronic enterocolitis is the leading cause of morbidity in colonies of captive rhesus macaques (Macaca mulatta). This study's aim was to identify the common enteric pathogens frequently associated with chronic enterocolitis in normal, immunocompetent rhesus monkeys and to elucidate the influence of this clinical syndrome on the host immune system. We analyzed the fecal specimens from 100 rhesus macaques with or without clinical symptoms of chronic diarrhea. Retrospective analysis revealed an increased incidence of Campylobacter spp. (Campylobacter coli and Campylobacter jejuni), Shigella flexneri, Yersinia enterocolitica, adenovirus, and Strongyloides fulleborni in samples collected from animals with chronic diarrhea (P < 0.05). The presence of additional enteric pathogens, such as Escherichia coli, carrying the eaeA intimin or Stx2c Shiga toxin virulence genes, Balantidium coli, Giardia lamblia, Enterocytozoon bieneusi, and Trichuris trichiura was found in all animals regardless of whether diarrhea was present. In addition, the upregulation of interleukin-1␣ (IL-1␣), IL-3, and tumor necrosis factor alpha cytokine genes, accompanied by an increased presence of activated (CD4 ؉ CD69 ؉ ) T lymphocytes was found in gut-associated lymphoid tissues collected from animals with chronic enterocolitis and diarrhea in comparison with clinically healthy controls (P < 0.05). These data indicate that chronic enterocolitis and diarrhea are associated, in part, with a variety of enteric pathogens and highlight the importance of defining the microbiological status of nonhuman primates used for infectious disease studies. The data also suggest that chronic colitis in rhesus macaques may have potential as a model of inflammatory bowel disease in humans.
Background and Aims-Lymphocytes populate the livers of infants with biliary atresia, but it is unknown whether neonatal lymphocytes regulate pathogenesis of disease. Here, we investigate this question by examining the role of T lymphocytes in the destruction of extrahepatic bile ducts of neonatal mice using an experimental model of biliary atresia.
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