Lymphocytes modulate peritoneal leukocyte recruitment in peritonitis.

OBJECTIVE AND DESIGN: To investigate the modulating role of lymphocytes in leukocyte recruitment in a murine model of peritonitis. MATERIALS OR SUBJECTS: RAG-1 knockout (KO) mice, NUDE mice and microMT KO mice were compared to their wild-type controls. TREATMENT: Mice were administered with 1 ml of Brewer's thioglycollate (BTG) and terminal peritoneal lavages were performed at 8, 24, 72 and 120 h after treatment. METHODS: Leukocyte numbers recruited at the different time points following a BTG administration were determined. Chemokine and cytokine levels were assessed by either ELISAs or cytometric bead array. RESULTS: RAG-1 KO mice (absent B and T cells) exhibited increased early neutrophil infiltration and blunted late monocyte/macrophage infiltration. NUDE mice (absent T cells) exhibited both increased neutrophil and monocyte/macrophage infiltration. In contrast, microMT KO mice (absent B cells) demonstrated reduced influx of both neutrophils and monocyte/macrophages. Chemokine analysis revealed various differences in important chemokines. CONCLUSIONS: These data suggest that T cells act to suppress leukocyte recruitment while B cells promote leukocyte recruitment.

Depletion of cells of monocyte lineage prevents loss of renal microvasculature in murine kidney transplantation.

BACKGROUND: Acute rejection increases the risk of late renal allograft loss with tubular atrophy, interstitial fibrosis, and microvascular rarefaction. Evidence supports a role for macrophages in promoting allograft injury, but the pathogenic mechanisms are unclear. Using a model of acute rejection, we sought evidence of macrophage-mediated endothelial cell cytotoxicity leading to loss of the renal microvasculature. METHODS: We used a transgenic conditional ablation strategy to deplete circulating monocytes and infiltrating renal macrophages after kidney transplantation. CD11b-DTR mice (FVB/nj strain) are transgenic for the human diphtheria toxin receptor gene under the control of the CD11b promoter. Administration of diphtheria toxin results in rapid ablation of circulating monocytes and resident/infiltrating renal macrophages. Transplants were performed between fully mismatched strains (Balb/c donor into control nontransgenic FVB/nj recipient; allograft group), between FVB/nj littermates (isograft group), and from Balb/c donors into CD11b-DTR mice (DT-treated group). Diphtheria toxin was administered at days 3 and 5, and the effect of monocyte/macrophage depletion on changes in renal microvasculature was determined at day 7. RESULTS: Conditional monocyte and macrophage ablation effectively depleted infiltrating macrophages in murine renal allografts at day 7. Macrophage ablation reduced histologic features of rejection (arteritis, tubulitis) and the accompanying rarefaction of peritubular capillaries at 7 days. The identification of macrophages immunopositive for inducible nitric oxide synthase implicated nitric oxide generation as a possible mechanism of endothelial cell cytotoxicity. CONCLUSION: These data indicate a significant role for macrophages in causing acute rejection-related tissue injury that is, at least in part, targeted to the microcirculation.

Identification of polymorphisms within Disrupted in Schizophrenia 1 and Disrupted in Schizophrenia 2, and an investigation of their association with schizophrenia and bipolar affective disorder.

We have undertaken a search for polymorphic sequence variation within Disrupted in Schizophrenia 1 and Disrupted in Schizophrenia 2 (DISC1 and DISC2), which are both novel genes that span a translocation breakpoint strongly associated with schizophrenia and related psychoses in a large Scottish family. A scan of the coding sequence, intron/exon boundaries, and part of the 5' and 3' untranslated regions of DISC1, plus 2.7 kb at the 3' end of DISC2, has revealed a novel microsatellite and 15 novel single nucleotide polymorphisms (SNPs). We have tracked the inheritance of four of the SNPs through multiply affected families, and carried out case-control association studies using the microsatellite and four common SNPs on populations of patients with schizophrenia or bipolar affective disorder versus normal control subjects. Neither co-segregation with disease status nor significant association was detected; however, we could not detect linkage disequilibrium between all these markers in the control population, arguing that an even greater density of informative markers is required to test rigorously for association in this genomic region.