Biomedical subjects

W Peters

Publications and source records attributed to W Peters.

At least 19 recordsLinked to original sources

PubMed2005

Long term complications in single and dual chamber pacing are influenced by surgical experience and patient morbidity.

OBJECTIVE: To determine how short and long term complication rates after pacemaker implantation are influenced by patient morbidity, operator experience, and choice of pacing system. DESIGN: Retrospective analysis of 1884 patients who received VVI (n = 610), VDD (n = 371), or DDD devices (n = 903) between 1990 and 2001. Follow up period was 64 (34) months. The influence of age, sex, coronary artery disease, myocardial infarction, reduced left ventricular (LV) function, right ventricular (RV) dilatation, atrial fibrillation, device type, and operator experience on operation time and complication rate were analysed. RESULTS: Operation time was prolonged in patients with coronary artery disease, inferior myocardial infarction, reduced LV function, and RV dilatation. Implantation of DDD pacemakers prolonged operation time, particularly among operators with a low or medium level of experience. The overall complication rate was 4.5%. Sixty seven per cent of these complications occurred within the first three months. Complication rate was increased by age, reduced LV function, and RV dilatation. Implantation of DDD systems led to a higher complication rate (6.3%) than implantation of VVI (2.6%) or VDD pacemakers (3.2%). These differences were present only among operators with a low or medium level of experience. CONCLUSIONS: Operation time and complication rate increased with age, impaired LV function, and RV dilatation. Complication rates were higher with DDD than with VVI or VDD implantation and were excessive among inexperienced but not experienced operators.

Age Factors↗

PubMed2005

The chemotherapy of rodent malaria. LXIII. Drug combinations to impede the selection of drug resistance, part 6: the potential value of chlorproguanil and dapsone in combination, and with the addition of artesunate.

Resistance is readily produced in rodent malaria using the single-dose, '2%-relapse technique' (2%RT) against the individual compounds chlorproguanil (CPG), chlorcycloguanil (CCG), cycloguanil, dapsone (DDS) and artesunate (ASN). Using the '4-day test', a low level of synergism or a simple additional action between CPG and DDS was observed with multiple dosing of these two compounds in a combination. Resistance to a 1 : 3 combination of CPG-DDS was selected in each of three parasite lines: Plasmodium berghei NK65, P. yoelii ssp. NS and P. chabaudi AS. Of these lines, P. chabaudi AS was found to be the most sensitive to the 1 : 3 combination in the 2%RT (and was also previously found to be the most sensitive when the compounds were used individually). Plasmodium chabaudi AS was also the line found most sensitive to a 7 : 21 : 300 combination of CPG-DDS-ASN (CDA). In mice infected with P. chabaudi AS, compared with the use of the individual components, the CPG-DDS combination only a gave a modest level of protection (as indicated by the increase in the time required to select resistance in the 2%RT) but the triple CDA combination was totally effective over the duration of the experiment. New pharmacokinetic data to be reported elsewhere indicate, however, that the antimalarial action of CPG in mice is exerted by a mechanism that is not associated with the drug's conversion to the antifolate triazine, CCG. The question thus arises as to how, in the present model, the protective action of CDA was effected. The present results nevertheless reinforce the hypothesis that a CDA combination, appropriately proportioned for human use, should be of practical value, in protecting the individual components, when used for the treatment of multidrug-resistant P. falciparum, and possibly other Plasmodium species, in endemic areas. Clinical trials, both with a CPG-DDS combination (Lapdap) and CDA, are currently under way in tropical Africa. Further studies are now required to determine whether DDS, CPG or an as-yet unidentified metabolite of CPG interact with ASN, and whether a simple double combination of ASN with one or other of these would be as protective, against the selection of resistance, as CDA.

Animals↗

PubMed2004

The chemotherapy of rodent malaria. LXII. Drug combinations to impede the selection of drug resistance, part 5: rates of development of resistance to some inhibitors of folate metabolism and to artesunate.

In recent years infection with chloroquine-resistant Plasmodium falciparum has been combatted with two long-acting antimalarials, pyrimethamine and sulfadoxine, in the combination known as Fansidar that exerts a strong, synergistic action on the asexual stages of the parasite. This second-line regimen, however, is failing increasingly because of the selection of resistant clones in endemic areas, and effective, safe, alternative drugs or drug combinations that are also affordable are urgently needed. Antimalarial drugs with shorter half-lives than those of pyrimethamine or sulfadoxine are likely to be slower to select resistant parasites. In the experiments reported here, the baseline in-vivo responses of rodent malarial parasites to chlorproguanil and proguanil and their active metabolites, chlorcycloguanil and cycloguanil, as well as those to dapsone and artesunate, were explored. In general, the most sensitive parasite to all of these compounds was P. chabaudi. When the drugs were used, individually, to select resistance via the '2%-relapse technique', relatively stable resistance to each was obtained in P. chabaudi as well as in P. berghei and P. yoelii ssp. NS, the last of these being also highly resistant to chloroquine. Of most concern was the rapidity and high level of resistance developed by P. chabaudi to artesunate. The experiments also validated the use of chlorcycloguanil or cycloguanil as surrogates for chlorproguanil or proguanil. Further studies to investigate the possible value of administering chlorproguanil-dapsone, with or without artesunate, are under way and will be reported separately.

Animals↗

PubMed2003

The chemotherapy of rodent malaria. LXI. Drug combinations to impede the selection of drug resistance, part 4: the potential role of 8-aminoquinolines.

The influence of combinations containing the blood schizontocides chloroquine (CQ) or mefloquine (MEF), together with the 8-aminoquinolines (8AQ) primaquine (PQ) or the new, long-acting compound, tafenoquine (TAF), on the rate of selection of resistance to the individual compounds was examined using the asexual, intra-erythrocytic stages in rodent malaria models. The two main procedures used were a 'serial technique' (ST) and the '2%- relapse technique' (2%RT). The ST provided evidence for the contention that a combination with PQ slowed the selection of resistance to CQ or MEF; it has been shown previously that synergism exists between CQ and either PQ or TAF in rodent malaria. Data obtained with the 2%RT, and three parasite lines derived from Plasmodium berghei N (the 238B line), P. chabaudi ASS (the 238C line) or P. yoelii ssp. NS (the 238Y line), indicated that resistance to TAF used alone is acquired rapidly under drug pressure and that this resistance is stable when selection pressure is removed. In the 2%RT, resistance to CQ developed when another line of P. chabaudi (AS15) was exposed to that compound alone, although more slowly than the development of resistance to TAF in the 238C line. However, treatment of a TC line of P. chabaudi, developed in a 2%RT using a combination of CQ with TAF, led to little resistance to either compound. A totally unforeseen phenomenon was the appearance of a high level of resistance to CQ in the 238C line of P. chabaudi that had been exposed only to TAF; this was not observed with the 238B or 238Y lines. Attention has been refocused recently on the use of 8AQ for prophylaxis in man. It remains to be determined if resistance in the asexual intra-erythrocytic forms is carried over to the other stages of the malarial life-cycle, especially the hepatic, pre-erythrocytic schizonts. The implications of the present results for the possible clinical deployment of 8AQ in the future are discussed. It is concluded that, whereas use of an 8AQ alone carries a high risk of selecting resistance, combinations containing 8AQ may have a place in the protection of blood schizontocides that are to be deployed in endemic areas. Furthermore, the inherent gametocytocidal action of the 8AQ should promote the reduction of transmission.

Aminoquinolines↗

PubMed2002

The chemotherapy of rodent malaria. LX. The importance of formulation in evaluating the blood schizontocidal activity of some endoperoxide antimalarials.

The activities of artemisinin (QHS) and a number of its semi-synthetic analogues, as well as Fenozan B07 (B07), a synthetic 1,2,4-trioxane, and arteflene (ATF), a synthetic surrogate of yingzhaosu, were compared in mice infected with drug-sensitive Plasmodium berghei or chloroquine-resistant P. yoelii ssp. NS. The studies were stimulated by the observation that B07, in certain aqueous preparations, appears to be equipotent by the subcutaneous (sc) or oral (po) routes in the rodent model but not in a simian model. In the rodent model, B07 was found to undergo rapid alteration (with a half-life of <24h) in an aqueous stock solution prepared using dimethyl sulphoxide (DMSO) to pre-dissolve the drug. Therefore, for all later experiments with aqueous preparations, the test material was newly formulated each day. In a carboxymethylcellulose formulation used as a 'standard suspending vehicle' (SSV), B07 and dihydroartemisinin (DIHYD) were found to be, respectively, one sixth and one 10th as active po as when the drugs were pre-dissolved in DMSO and then diluted with water. ATF in DMSO given po was less than one 20th as active as when used sc in the rodent model, and this drug in SSV was almost inactive po. The relatively low oral activity of these three compounds (especially DIHYD and ATF) may be attributable to extensive first-pass metabolism in the mouse. Oral beta-artemether (AM) and beta-arteether (AE) were highly active when used in SSV. ATF has been found to have low activity in simian models and clinical trials because of its poor absolute bio-availability. In in-vivo studies of the blood schizontocidal action of anti-malarials, in rodent malaria models, the data collected on the structure-activity relationships (SAR) of the drugs must be viewed critically when selecting specific compounds from a chemical series for further development. A study of the influence of drug formulation on the activity of other, novel antimalarials is crucial to the evaluation of the drugs, and merits high priority.

Administration, Oral↗

PubMed2002

Novel and challenging infections of man. A brief overview.

The greatest challenge to human health of recent times is the pandemic caused by the retroviruses known as HIV1 and HIV2. These have unleashed a plethora of opportunistic infections with organisms ranging from other viruses to helminths, some of which are newly recognised taxa or organisms never before identified as serious pathogens of man. Animal and bird migration as well as human travel and international trade have extended, to an alarming degree, the dissemination of other viral infections. Malaria is an increasing global challenge to human health, a reversal of the downward trend that was achieved in the latter half of the 20th century. Moreover, evidence is currently accumulating for the existence of a fifth species of Plasmodium in man. In the bacterial and protozoal fields, other novel organisms are being described. Powerful new tools of molecular biology are being deployed to probe parasite genetics, for example to reveal the genome of Plasmodium falciparum. These and molecular immunological techniques are also helping to resolve puzzling taxonomic questions, as well as aiding epidemiological studies that are revealing the unforeseen scale of human infection with a number of parasitic helminths in both tropic and temperate climatic areas. This paper presents a brief review of the major, as well as some of the relatively minor changes and advances of recent decades.

Arbovirus Infections↗

PubMed2001

Chemokine receptor 2 serves an early and essential role in resistance to Mycobacterium tuberculosis.

Although the protective cellular immune response to Mycobacterium tuberculosis requires recruitment of macrophages and T lymphocytes to the site of infection, the signals that regulate this trafficking have not been defined. We investigated the role of C-C chemokine receptor 2 (CCR2)-dependent cell recruitment in the protective response to M. tuberculosis. CCR2(-/-) mice died early after infection and had 100-fold more bacteria in their lungs than did CCR2(+/+) mice. CCR2(-/-) mice exhibited an early defect in macrophage recruitment to the lung and a later defect in recruitment of dendritic cells and T cells to the lung. CCR2(-/-) mice also had fewer macrophages and dendritic cells recruited to the mediastinal lymph node (MLN) after infection. T cell migration through the MLN was similar in CCR2(-/-) and CCR2(+/+) mice. However, T cell priming was delayed in the MLNs of the CCR2(-/-) mice, and fewer CD4(+) and CD8(+) T cells primed to produce IFN-gamma accumulated in the lungs of the CCR2(-/-) mice. These data demonstrate that cellular responses mediated by activation of CCR2 are essential in the initial immune response and control of infection with M. tuberculosis.

Animals↗

PubMed2001

Impact of breast carcinoma on African-American women: the Detroit experience.

BACKGROUND: National and regional population-based data have demonstrated substantially worse outcome in African-American patients with breast carcinoma when compared with white patients, as well as a younger age distribution among African-American patients with breast carcinoma. The extent to which various socioeconomic, environmental, lifestyle, and genetic factors interact to account for this ethnicity-related disparity in survival is poorly understood. Greater than one-half of the inner-city population of Detroit, Michigan is African American, and greater metropolitan Detroit has been one of the contributing registries for the Surveillance, Epidemiology, and End Results (SEER) program since its inception in 1973. The impact of breast carcinoma on African Americans in the Detroit area is therefore well documented and provides significant insight into the history, epidemiology, and biology of this major public health care problem. METHODS: A review of the medical literature published over the past 20 years regarding African-American patients with breast carcinoma was performed. The pertinent findings were summarized in the context of advances made in breast carcinoma screening, treatment, and risk reduction during that period. RESULTS: The large African-American population of Detroit is a major factor contributing to the excessive breast carcinoma mortality rate reported for this city, which is one of the highest in the United States. Improvements in early detection of breast carcinoma by using screening mammography have been apparent in the earlier stage distributions of breast carcinoma observed in both white and African-American patients; however, progress has lagged substantially for the latter group. Detroit SEER registry data also have shown a younger age distribution of African-American patients with breast carcinoma and higher rates of estrogen receptor negative tumors. Finally, preliminary data from health maintenance organizations have suggested improved breast carcinoma outcome for African Americans who possess greater socioeconomic benefits, but disparities in disease stage at presentation persist. CONCLUSIONS: The diverse Detroit community is ideally suited for breast carcinoma screening programs and clinical investigations that seek to address and overcome ethnicity-related survival disparities and barriers to health care. Findings from these studies can be correlated with results from similar projects in other geographic areas.

Black or African American↗

PubMed2001

Low infectious morbidity after intensive chemotherapy and autologous peripheral blood progenitor cell transplantation in the outpatient setting for women with breast cancer.

Autologous peripheral blood progenitor cell (PBPC) transplantation is increasingly employed in the outpatient setting, yet data on early complications following PBPC transplantation are scant. We evaluated 105 women with high-risk primary or metastatic breast cancer who were treated at a single institution during 1996--1997. The mean duration of neutropenia (absolute neutrophil count, <500 cells/mm(3)) was 7.5 days. Twenty-nine percent of women remained afebrile throughout the neutropenic period. Of the remaining 71%, most (64 of 75) had fever of unknown origin. Infections, mostly of mild severity, occurred in 34% of women; these infections included bacteremia due to gram-positive organisms, catheter site infection, cellulitis, pneumonia, oral candidiasis, herpes simplex virus infection, and vaginitis. Fifty percent of PBPC transplant recipients required hospital admission, usually because of persistent fever; the mean duration of hospitalization was 3 days. No deaths or serious adverse events occurred. Such reduced infectious morbidity may be a consequence of minimal oral and/or gastrointestinal mucositis associated with the conditioning regimen and broad-spectrum antimicrobial prophylaxis used for this patient population.

Adult↗

PubMed2001

The peri-implant breast capsule: an immunophenotypic study of capsules taken at explantation surgery.

Silicone-based breast implants continue to be the focus of many studies attempting to correlate implant failure to clinical and pathological factors. Routine pathology of peri-implant capsule is extensively described in the literature. The actual significance of the cellular events remains unconfirmed, particularly with reference to clinical outcome. This study reviews our experience with explanted capsules. The study makes specific reference to the immunohistochemistry of the cells participating in the capsule and the significance of the immunophenotypic characterization of these cells to clinical outcome. The use of a wide selection of immunomarkers for T and B lymphocytes and histiocytes provided no supporting evidence for local cell participation in the capsule, which may indicate the presence of an immunological reaction present in the capsule at the time of explantation. One was only able to confirm the presence of a low grade inflammatory process and progression to fibrosis and calcification over time. Statistical correlation was obtained only between Baker grade of capsular contracture and CD3/CD68 immunomarker positivity. CD45RO did show correlation with pain. No correlation was demonstrated with calcification. The results obtained in this study highlighted the need for further investigations into the mechanism of histiocyte and fibrocyte recruitment and activation in the capsule, a possible source of pain and contracture, which is a serious long-term clinical finding leading to the necessity for explantation.

Adult↗

PubMed2001

Immunization with the adjuvant MF59 induces macrophage trafficking and apoptosis.

The mechanisms associated with the immunostimulatory activity of vaccine adjuvants are still poorly understood. We have undertaken a study to determine whether antigen-presenting cell trafficking is modified by administration of the submicron emulsion adjuvant MF59. We investigated the fate of inflammatory macrophages after intramuscular injection of the antigen herpes simplex virus gD2 with fluorescence-labeled MF59. A homogeneous population of macrophages infiltrated the muscle, internalized adjuvant and expressed markers characteristic of mature macrophages over a 48-h period. Macrophage influx to the injection site was reduced by 70% in mice deficient for the chemokine receptor 2 (CCR2). Two distinct cell populations were shown to contain fluorescence-labeled MF59 in the draining lymph node at 48 h post injection. The first population had a round morphology, exhibited bright fluorescence, was located in the subcapsular sinus, and was apoptotic. The second population had a dendritic morphology, was weakly fluorescent, and was located in the T cell area where adjuvant-containing apoptotic bodies identified by TUNEL labeling were present. We propose that lymph node-resident dendritic cells can acquire antigen and MF59 after intramuscular immunization by uptake of the apoptotic macrophages.

Adjuvants, Immunologic↗

PubMed2001

Delayed restoration of atrioventricular synchrony with beat-to-beat mode switch.

This case report describes a patient with complete AV block and a VDD pacemaker who experienced repetitive episodes of symptomatic bradycardia. Episodes occurred due to activation of an automatic beat-to-beat mode switch algorithm. After mode switch to VDI operation, the pacemaker failed to immediately switch back to AV synchronous pacing when regular sinus rhythm (> or = 100 beats per minute) resumed despite adequate P wave sensing. Dizziness was felt for up to several minutes of asynchronous pacing at the lower rate limit until VDD mode was restored. Episodes were completely eliminated by programming the mode switch function from an automatic beat-to-beat algorithm to a fixed rate algorithm.

Algorithms↗

PubMed2001

Incidence and predictors of pacemaker dysfunction with unipolar ventricular lead configuration. Can we identify patients who benefit from bipolar electrodes?

Unipolar ventricular leads were implanted in a considerable percentage of pacemaker recipients. There is little information on incidence and risk factors for unipolar pacemaker dysfunction using modern lead designs. Included in a cross-sectional analysis were 682 patients who fulfilled the following criteria: chronically implanted bipolar ventricular leads (> 1 year), intraoperative stimulation threshold < 1.0 V/0.5 ms, and potential amplitude > 6 mV. Incidences of chest wall stimulation (CWS) at an output of twice the amplitude threshold and of myopotential oversensing (MPO) at a sensitivity of half the sensing threshold were assessed. Energy (0.60 [0.72] vs 0.63 [0.81] microJ) and sensing thresholds (8.31 [3.18] mV vs 8.47 [3.47] mV) did not differ between uni- and bipolar modes. While all pacemakers worked properly during bipolar configuration, malfunctions were observed in 5.9% of patients during unipolar configuration (CWS = 1.9%, MPO = 4.2%). Patient age > 76 years (hazard ratio HR 8.2; P < 0.001), heart failure > or = NYHA Class II (HR 3.8; P < 0.001), and an antiarrhythmic therapy with Class I or III drugs (HR 3.3; P = 0.002) were independently associated with the occurrence of unipolar pacemaker dysfunction. Use of steroid-eluting leads reduced the probability of pacemaker dysfunction (HR 0.45; P = 0.03). Risk factors for unipolar ventricular pacemaker malfunction were higher age, heart failure, and antiarrhythmic drug therapy. Particularly in these patients, use of bipolar ventricular leads is beneficial.

Adult↗

PubMed2001

Cost-effectiveness of dual-chamber pacemaker therapy: does single lead VDD pacing reduce treatment costs of atrioventricular block?

AIMS: Implantation of single-lead VDD pacemakers is an established alternative to DDD pacing in patients with atrioventricular block. This study compares the long-term costs of both systems. METHODS AND RESULTS: Three hundred and sixty patients with atrioventricular block received VDD or DDD pacemakers in alternating order. Primary costs of implantation included: devices, leads and operation material, surgeons, nurses, medical technicians, and hospitalization. The mean cost of an uncomplicated DDD pacemaker implantation was defined as 1000 virtual cost-units (CU). Costs of pacemaker related complications or re-operations as well as upgrades from VDD to DDD devices were considered secondary costs and assessed during a mean follow-up period of 42+/-15 months. Pacing efficacy was assessed by event-free survival with maintained atrioventricular synchronized pacing mode. Costs of pacemaker devices were not different (639+/-26 CU in VDD vs 641+/-32 CU in DDD, ns). However, due to lower costs of lead hardware (102+/-10 CU in VDD vs 133+/-14 CU in DDD, P<0.001) and shorter implantation procedures (44.3+/-5.1 min vs 74.4+/-13.5 min, P<0.001), costs of an uncomplicated implantation were 8.9% lower in the VDD group (911+/-35 CU vs 1000+/-39 CU, P<0.001). A smaller complication rate in the VDD group led to a 16.1% reduction of secondary costs (26+/-17 CU year(-1)vs 31+/- 25 CU year(-1), P=0.024). Event-free survival did not differ between groups (83.4% in VDD vs 84.9% in DDD, ns). CONCLUSION: Use of single-lead VDD pacemakers achieves significant reduction of implantation and follow-up costs without loss of therapeutic efficacy compared to conventional DDD systems.

Aged↗

PubMed2001

Calcification properties of saline-filled breast implants.

Three patients requested explantation of their saline-filled breast implants. Bilateral calcification had occurred in all six implants. Four of the implants were manufactured by McGhan Corporation (Santa Barbara, Calif.), and two, by the Simaplast Company (Toulon, France). All implants had been inserted in the subglandular plane and had been in place for 7 to 23 years. At the time of explantation, patients were 32, 34, and 44 years old. Calcification on the surface of the implants and capsules was analyzed. Implant surface calcification was clinically evident on all six implants, appearing as ivory-colored, tenaciously adherent deposits, only on the anterior surface of the implant. Capsular calcification, which was observed only microscopically, was characterized by poorly organized, irregularly shaped, calcified agglomerates; this calcification also occurred only on the anterior surface of the capsule, adjacent to the area of calcification on the implant. Ultrastructural analysis of scrapings from the implant surface showed large, electron-dense aggregates of crystals, with individual crystals measuring approximately 40 x 10 x 10 nm. In contrast, capsular calcification was characterized by two patterns of deposition, spherulitic aggregates of needle-shaped crystals and areas of metaplastic bone. The individual crystals were approximately 40 x 10 x 10 nm. Energy-dispersive x-ray spectroscopy of specimens from the areas of calcification on the implant and capsule surfaces demonstrated calcium and phosphorus. Electron diffraction of crystals from the implant and capsule surfaces demonstrated the D-spacings characteristic of calcium apatite. There were many differences between the calcification properties of these six saline implants and those of silicone gel implants. For example, mineralization has not been observed on the surface of gel implants, but in these saline implants it occurred primarily on the implant surface. Also, capsular calcification has been observed clinically in gel implants across the surface of the capsule (except at the site of attachment of a Dacron patch), but in this study it was observed only microscopically and was located on the anterior surface of the capsule, adjacent to the area of calcification on the implant. In addition, crystals 100 times larger than those observed on the six saline implant capsules have been observed on the surface of gel implant capsules. A model is presented to explain the mechanism of calcification associated with breast implants and to explain the observed differences between saline-filled and gel-filled implants.

Adult↗

PubMed2001

Involvement of chemokine receptor 2 and its ligand, monocyte chemoattractant protein-1, in the development of atherosclerosis: lessons from knockout mice.

Blood monocytes are the precursors of the lipid-laden foam cells that are the hallmark of early atherosclerotic lesions, but the signals that initiate their recruitment to the vessel wall are poorly understood. Here, we review in vivo studies in genetically altered mice that support the notion that monocyte chemoattractant protein-1 (a member of the chemokine family of chemotactic cytokines) and chemokine receptor 2 (its cognate receptor) play important roles in this recruitment. An unexpected finding in chemokine receptor 2-knockout mice was the diminished production of interferon-gamma, which is a potent macrophage activator. The basis of this cytokine defect is not yet clear, but suggests that chemokines may influence atherosclerotic lesion development at several levels. Understanding the roles of chemokines and cytokines in atherogenesis may provide a basis for the development of future therapeutic agents that are aimed at interrupting monocyte recruitment and activation.

Animals↗

PubMed2001

Targeted deletion of CX(3)CR1 reveals a role for fractalkine in cardiac allograft rejection.

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.

Animals↗

PubMed2000

A mechanism for the impaired IFN-gamma production in C-C chemokine receptor 2 (CCR2) knockout mice: role of CCR2 in linking the innate and adaptive immune responses.

We have recently shown that mice with a targeted disruption of CCR2, the receptor for monocyte chemoattractant protein-1, have markedly impaired recruitment of macrophages to sites of inflammation. An unexpected finding in the CCR2(-/-) mice was a dramatic decrease in the production of IFN-gamma after challenge with purified protein derivative of Mycobacterium bovis. In this study, we have investigated the mechanism of this cytokine production defect. In vitro, direct activation of splenocytes with CD3/CD28 Abs failed to reveal any differences in IFN-gamma production between CCR2(+/+) and CCR2(-/-) mice. However, after immunization, the number of Ag-specific, IFN-gamma-producing cells in the draining lymph nodes was decreased by 70% in the CCR2(-/-) mice, suggesting an in vivo trafficking defect. Direct measurement of cell trafficking with fluorescently labeled CFA revealed a marked decrease in the number of monocytes/macrophages migrating to the site of immunization and to the draining lymph nodes in the CCR2(-/-) mice. The data suggest that impaired trafficking of APCs in the CCR2(-/-) mice contributes to the defect in IFN-gamma production. These data support the idea that CCR2-positive monocytes/macrophages are critical in linking the innate and adaptive immune responses.

Adaptation, Physiological↗