The genetic deficiency of iNOS has not been investigated in vivo. These findings have been interpreted as a molecular trigger for interstitial nephritis ( 20– 22). In vitro studies have previously reported the activation of a broad range of inflammatory genes, such as those for transcription factor NF-κB, inducible nitric oxide synthase (iNOS), monocyte chemotactic protein-1, and tumor necrosis factor alpha, by renal tubular cells in response to exposure to leptospire-derived products. We have also reported the association between high serum levels of nitric oxide (NO) and the severity of renal involvement in patients with severe leptospirosis ( 9) Renal production of NO could be involved in transport defects in renal tubular cells ( 4). In our previous report, the C57BL/6 background mice exhibited high leptospiral loads in kidney samples and developed severe inflammatory lesions, while these features were not observed in the BALB/c mice ( 15). Mutations in both Prkdc and Rag-1 genes are listed as causes of human SCID. Thus, Rag1 KO mice are unable to generate specific B and T lymphocytes. Rag1 KO mice lack a gene that plays an important role in the rearrangement and recombination of the genes of immunoglobulin and T-lymphocyte receptor molecules during the process of VDJ recombination. The strain is similar to the BALB/c strain except that it carries the Igh-1b allele from the C57BL/Ka strain. CB17 SCID mice are unable to produce functional B and T lymphocytes due to a mutation in the Prkdc gene, which encodes a DNA-dependent protein kinase involved in DNA double-strand break repair and recombination. In this study, we reproduced these experiments in the following murine models: CB17 SCID and C57BL/6 recombination activating gene 1 ( Rag1) KO mice. However, the observation of PH in SCID mice is not reliable because it was observed in the C3H/HeJ mouse strain background ( 19) but not the C3H background ( 14). Rats are the prototype model of resistance to acute lethal infection ( 3), but consistent with the observation from SCID mice, rats treated with cyclophosphamide (which suppresses humoral immunity) develop PH ( 18). However, the involvement of auto-antibodies in PH was countered by a description of lethal PH in experimentally infected severe combined immunodeficiency (SCID) mice lacking functional B- and T-lymphocyte subsets ( 19). These data provide evidence that PH in leptospirosis may not be related only to autoimmune mechanisms.Ī potential role for autoimmunity in leptospirosis-associated PH was suggested based on observations in the guinea pig model of leptospirosis ( 12) and, to a lesser extent, in human patients with severe pulmonary hemorrhage syndrome ( 7). Of note, the absence of functional B- and T-cell lymphocytes did not preclude the occurrence of PH. In conclusion, the loss of the Inos gene had a negligible effect on the outcome of leptospiral infection, although we observed a reduced susceptibility for interstitial nephritis in this group. There was no evidence of PH in the WT controls. PH was observed in 57 and 94% of Rag1 KO mice and in 83 and 100% of SCID mice, using inoculum doses of 10 7 and 10 6 leptospires, respectively. All of the Rag1 KO and SCID animals died of acute leptospirosis, whereas all of the WT mice survived. The frequency and severity of nephritis was significantly lower in the Inos KO mice. The Inos KO and WT mice survived with no clinical symptoms of leptospirosis. The animals used were Inos KO mice, recombination activating gene 1 ( Rag1) KO mice, CB17 severe combined immunodeficiency (SCID) mice, and the respective wild-type (WT) C57BL/6 and BALB/c controls. We studied the outcome of infection by the virulent Leptospira interrogans serovar Copenhageni strain Cop. The aims of this study were to investigate the frequency of pulmonary hemorrhage (PH) in mice unable to produce functional B and T lymphocytes and to explore the effect of an inducible nitric oxide synthase gene ( Inos) knockout (KO) on the frequency/severity of interstitial nephritis in vivo.
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