Fractalkine (Fk) is a structurally unusual member of the chemokine family. To determine its role in vivo, we generated mice with a targeted disruption of CX 3 CR1, the receptor for Fk. CX 3 CR1 -/-mice were phenotypically indistinguishable from wild-type mice in a pathogen-free environment. In response to antibody-induced glomerulonephritis, CX 3 CR1 -/-and CX 3 CR1 +/+ mice had similar levels of proteinuria and injury. CX 3 CR1 -/-and CX 3 CR1 +/+ mice also developed similar levels of disease in myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis. We performed heterotopic MHC class I/II cardiac transplants from BALB/c mice into C57BL/6 mice. In the absence of cyclosporin A (CsA), there was no difference in graft survival time between CX 3 CR1 -/-and CX 3 CR1 +/+ recipient mice. However, in the presence of subtherapeutic levels of CsA, graft survival time was significantly increased in the CX 3 CR1 -/-mice. Characterization of cells infiltrating the grafts revealed a selective reduction in natural killer cells in the CX 3 CR1 -/-recipients in the absence of CsA and a reduction in macrophages, natural killer cells, and other leukocytes in the presence of CsA. We conclude that Fk plays an important role in graft rejection. The development of CX 3 CR1 antagonists may allow reductions in the doses of immunosuppressive drugs used in transplantation.

Fractalkine (Fk) is a structurally unusual member of the chemokine family. To determine its role in vivo, we generated mice with a targeted disruption of CX 3 CR1, the receptor for Fk. CX 3 CR1 -/-mice were phenotypically indistinguishable from wild-type mice in a pathogen-free environment. In response to antibody-induced glomerulonephritis, CX 3 CR1 -/-and CX 3 CR1 +/+ mice had similar levels of proteinuria and injury. CX 3 CR1 -/-and CX 3 CR1 +/+ mice also developed similar levels of disease in myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis. We performed heterotopic MHC class I/II cardiac transplants from BALB/c mice into C57BL/6 mice. In the absence of cyclosporin A (CsA), there was no difference in graft survival time between CX 3 CR1 -/-and CX 3 CR1 +/+ recipient mice. However, in the presence of subtherapeutic levels of CsA, graft survival time was significantly increased in the CX 3 CR1 -/-mice. Characterization of cells infiltrating the grafts revealed a selective reduction in natural killer cells in the CX 3 CR1 -/-recipients in the absence of CsA and a reduction in macrophages, natural killer cells, and other leukocytes in the presence of CsA. We conclude that Fk plays an important role in graft rejection. The development of CX 3 CR1 antagonists may allow reductions in the doses of immunosuppressive drugs used in transplantation.

Urinary concentrations of interleukin-1 alpha (IL-1 alpha) and interleukin-1 receptor antagonist (IL-lra) standardized to urinary creatinine concentrations were studied. The median standardized IL-1 alpha creatinine quotient in children with first-time acute pyelonephritis was 3.6 pg/mumol, but was nondetectable in children with recurrent pyelonephritis, children with non-renal febrile conditions and children convalescent after acute pyelonephritis (p < 0.05-0.01). IL-lra levels were also significantly higher in children with acute first-time pyelonephritis (median of 239 pg/mumol) compared to these three groups of children (p < 0.01-0.001). The highest urinary IL-lra levels, however, were found in the healthy controls (median value 1.019; p < 0.001). Both cytokines were higher among children younger than one year compared to older children. The acute IL-1 alpha creatinine quotients were lowest in children with uptake defects on 99mTC-dimercaptosuccinic acid (DMSA) scintigraphy both during the acute infection (reflecting the acute inflammation) (p < 0.001) and 1 year after the acute infection (reflecting permanent kidney scarring) (p < 0.001). In conclusion, persisting high urinary levels of IL-1 alpha were associated with less renal inflammation and scarring.

The relationship between urine interleukin-6 (IL-6) and interleukin-8 (IL-8)/creatinine quotients and 99mTc-dimercaptosuccinic acid (DMSA) scintigraphy, performed within 10 days of acute first-time pyelonephritis and after 1 year, was studied in 41 children. The urine IL-6 and IL-8/creatinine quotients were also related to the urine N-acetyl-beta-D-glucosaminidase (NAG) and albumin/creatinine quotients. Presence of DMSA uptake defects, reflecting local inflammation, in children in the acute phase of pyelonephritis, were associated with elevated urine IL-6/creatinine quotients (median 27 pg/mumol); in children without DMSA changes there was no increase in quotients (median non-detectable) (P < 0.05). Persistent DMSA changes at the 1-year follow-up, probably reflecting renal scarring, were only seen in children with increased urine IL-6/creatinine quotients in the acute phase (P < 0.01). No correlation was found between urine IL-8 and DMSA uptake defects. Vesicoureteral reflux (VUR) at 6-8 weeks did not correlate with the urine cytokine levels in the acute phase. The urine excretion of NAG and albumin, reflecting renal dysfunction, was associated with values of both urine IL-6 and IL-8/creatinine quotients, but not with DMSA defects or VUR. Thus, the initial urine IL-6/creatinine quotients might be used as an indicator of risk for persistent renal damage in acute pyelonephritis.

Interleukin-6 (IL-6) and interleukin-8 (IL-8) are important mediators of the inflammatory response in serious bacterial infections. We studied the levels of these two cytokines (standardised for urinary creatinine) in the urine of infants and children during and 6 weeks after acute pyelonephritis and in non-renal febrile controls and healthy children without apparent infection. IL-6 was detected in the urine of 52% of children with pyelonephritis compared with 15% of other children (P < 0.001). The median urinary IL-6 level in acute pyelonephritis was 4 pg/mumol compared with undetectable levels in the control group (P < 0.001). IL-8 was detected in 98% of children with pyelonephritis and 42% of other children (P < 0.001). The median concentration of IL-8 was 188 pg/mumol in pyelonephritis; it was undetectable in controls (P < 0.001). IL-8 levels were higher in children less than 1 year of age (P < 0.001).