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J A Hedrick

Publications and source records attributed to J A Hedrick.

At least 37 records · Page 2Linked to original sources
PubMed1999

Recent advances in chemokines and chemokine receptors.

Chemokines are a superfamily of small cytokine-like molecules which have been described primarily on the basis of their ability to mediate the migration of verious cell types, particularly those of lymphoid origin. The receptors for these molecules are all seven-transmembrane domain G protein-coupled receptors that have historically been excellent targets for small-molecule drugs. This fact, coupled with the advent of large-scale DNA database mining and the recognition that chemokine receptors are also coreceptors for HIV, has driven discovery in this field at a tremendous rate. This process has included not just an expansion of the number of known chemokines and chemokine receptors, but also a greater appreciation for the variety of functions that chemokines are involved in. We review here the molecules that have come from the most recent years of chemokine research as well as many of the new functions that have been ascribed to them.

Amino Acid Sequence↗
PubMed1998

The chemokine receptor CCR8 is preferentially expressed in Th2 but not Th1 cells.

In this paper we report on the cloning and characterization of mouse CCR8. Like its human homologue, it is predominantly expressed in the thymus. In the periphery, murine CCR8 mRNA was found most abundantly expressed in activated Th2-polarized cells and in NK1.1+ CD4+ T cells. Human CCR8 is also preferentially expressed in human Th2-polarized cells and clones. This pattern of expression suggests that CCR8 is part of a Th2-specific gene expression program. The CCR8 ligands I-309 and its mouse homologue T cell activation gene 3 (TCA-3) are potent chemoattractants for Th2-polarized cells. Taken together, these observations strongly suggest that CCR8 plays a role in the control of Th2 responses, and may represent a potential target for treatment of allergic diseases.

Amino Acid Sequence↗
PubMed1998

Characterization of a novel CC chemokine, HCC-4, whose expression is increased by interleukin-10.

We have identified and characterized a human beta (CC) chemokine, designated HCC-4, that is most closely related to HCC-1 and which demonstrates chemotactic activity for monocytes. Northern analysis of multiple tissue blots and of activated monocytes mRNA shows expression of a 500-bp mRNA. A 1,500-bp mRNA was highly expressed in monocytes activated 12 hours in the presence of interleukin-10 (IL-10) but was absent in monocytes activated for only 1 hour regardless of the presence or absence of IL-10. The upregulation of expression in the presence of IL-10 is in contrast to the downregulatory effects of IL-10 on expression of most other chemokines. Recombinant HCC-4 demonstrated chemotactic activity for human monocytes and THP-1 monocyte cells but not for resting lymphocytes or neutrophils. HCC-4 also induced a Ca2+ flux in THP-1 cells that was desensitized by prior exposure to RANTES. Taken together, these data indicate that HCC-4 is a novel chemokine whose expression is uniquely upregulated by IL-10.

Amino Acid Sequence↗
PubMed1998

Lymphotactin.

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Amino Acid Sequence↗
PubMed1997

Identification and characterization of a novel beta chemokine containing six conserved cysteines.

The chemokines are emerging as a diverse and expanding family of cytokines. In this study, we report the identification of a novel beta (CC) chemokine that exhibits an unusual pattern of six conserved cysteines and was thus designated 6Ckine. The primary amino acid sequence of 6Ckine is highly conserved in humans, mice, and pigs and contains the expected four cysteines characteristic of the beta chemokine family plus two additional carboxyl-terminal cysteines. Expression of human 6Ckine appears to be restricted to lymphoid organs, particularly lymph node, spleen, and appendix, while murine 6Ckine has a broader tissue distribution with the highest mRNA levels found in spleen and lung. Recombinant murine 6Ckine was chemotactic in vitro for thymocytes and activated T cells, but not for B cells, macrophages, or neutrophils. Together these data demonstrate that 6Ckine is a novel member of the chemokine superfamily.

Amino Acid Sequence↗
PubMed1997

Lymphotactin is produced by NK cells and attracts both NK cells and T cells in vivo.

Injection of lymphotactin (Lptn) into the peritoneum caused an influx of lymphocytes at 24 h. Phenotypic analysis of the cellular influx showed that a large proportion of these cells were T lymphocytes; however, a large number of NK cells was also present. This effect of murine Lptn (mLptn) was specific since the cellular influx was blocked with a mLptn-specific mAb. Similar results were observed when Lptn was injected s.c. and the tissue was analyzed by immunohistochemistry using an anti-CD3epsilon mAb. Microchemotaxis assays confirmed that murine NK cells respond to mLptn, and also showed human NK clones to be similarly responsive to recombinant human Lptn (rhLptn). Immunohistochemical analysis of IL-2-activated murine NK cells and Northern analysis of human NK clones revealed that these cells also produce Lptn, suggesting that a self-regulatory migration mechanism exists in NK cells. Together these data confirm, in vivo, the lymphocyte specificity of Lptn previously observed in vitro and extend its chemotactic effects to the NK cell lineage. We also investigated the functional consequences of truncating the carboxyl terminus of hLptn. This truncated molecule (which is missing the carboxyl-terminal 22 amino acids of hLptn) had no detectable activity on human PBLs. In addition, while hLptn was found to attract murine splenocytes in vitro, the carboxyl-terminal truncated hLptn was again inactive on murine splenocytes. This observation indicates the presence of structural features in the carboxyl terminus of Lptn that are necessary for its biologic activity.

Amino Acid Sequence↗
PubMed1997

A study of 5-day cefdinir treatment for streptococcal pharyngitis in children. Cefdinir Pediatric Pharyngitis Study Group.

OBJECTIVE: To compare the safety and efficacy of a 5-day regimen of cefdinir with those a conventional 10-day regimen of penicillin V for the treatment of streptococcal pharyngitis in children. DESIGN: Investigator-blind, randomized controlled trial. SETTING: Primary care, ambulatory. PATIENTS: Children aged 1 to 12 years with signs and symptoms of pharyngitis and a positive result on a rapid screening test for Streptococcus pyogenes (ie, a convenience sample). Four hundred eighty-two patients were enrolled in the study, and 440 were clinically and microbiologically evaluable. The most common reasons patients were nonevaluable were failure to return for specified visits and noncompliance with the administration of the medication; 2 patients receiving penicillin V discontinued use of the drug because of adverse events. INTERVENTION: Patients were randomized to receive either 7-mg/kg cefdinir, twice daily, for 5 days or 10-mg/kg penicillin V potassium, 4 times daily, for 10 days. MAIN OUTCOME MEASURES: The eradication of S pyogenes and the clinical cure of the signs and symptoms of pharyngitis, both determined 5 to 10 days after the completion of therapy. RESULTS: Streptococcus pyogenes was eradicated in 201 (90%) of the 224 patients receiving cefdinir and 155 (72%) of the 216 patients receiving penicillin V (95% confidence interval [CI], 10.7%-25.1%; P < .001). The clinical cure rates were 92% and 91% in the groups receiving cefdinir and penicillin V, respectively (95% CI, -4.5% to 6.1%; P = .80). Adverse events, regardless of the opinion of the investigator about their relationship to the study medication, occurred in 12.5% of the patients receiving cefdinir and 13.6% of the patients receiving penicillin V (P = .69). CONCLUSIONS: A 5-day regimen of cefdinir eradicated a higher proportion of S pyogenes than a 10-day regimen of penicillin V. No difference was noted between the regimens for clinical outcomes or adverse event rates.

Adolescent↗
PubMed1997

TECK: a novel CC chemokine specifically expressed by thymic dendritic cells and potentially involved in T cell development.

A novel CC chemokine was identified in the thymus of mouse and human and was designated TECK (thymus-expressed chemokine). TECK has weak homology to other CC chemokines and maps to mouse chromosome 8. Besides the thymus, mRNA encoding TECK was detected at substantial levels in the small intestine and at low levels in the liver. The source of TECK in the thymus was determined to be thymic dendritic cells; in contrast, bone marrow-derived dendritic cells do not express TECK. The murine TECK recombinant protein showed chemotactic activity for activated macrophages, dendritic cells, and thymocytes. We conclude that TECK represents a novel thymic dendritic cell-specific CC chemokine that is possibly involved in T cell development.

Amino Acid Sequence↗
PubMed1997

Equivalent efficacy and reduced occurrence of diarrhea from a new formulation of amoxicillin/clavulanate potassium (Augmentin) for treatment of acute otitis media in children.

OBJECTIVE: To compare the safety and efficacy, in treating acute otitis media (AOM) in children, of a new formulation of amoxicillin/clavulanate potassium (Augmentin) oral suspension providing 45/6.4 mg/kg/day and administered twice daily (bid) for 5 and 10 days, respectively, with the safety and efficacy of the original formulation providing 40/10 mg/kg/day and administered three times daily (tid) for 10 days. STUDY DESIGN: Eight hundred sixty-eight children ages 2 months to 12 years with AOM were randomly assigned to one of the three treatment groups. Stringent criteria were used for the diagnosis of AOM and for determinations of "cure" and "improvement." Subjects were reexamined on Days 12 to 14 and 32 to 38. RESULTS: Among subjects whose treatment and follow-up conformed fully to protocol, the proportion of treatment successes (clinically cured or improved) on Days 12 to 14 was 78.8% (149 of 189) in the tid 10-day group, 86.5% (154 of 178) in the bid 10-day group and 71.1% (140 of 197) in the bid 5-day group. Corresponding values on Days 32 to 38 were 64.2% (95 of 148) in the tid 10-day group, 63.1% (94 of 149) in the bid 10-day group and 57.8% (93 of 161) in the bid 5-day group. None of the differences between the tid 10-day regimen and either of the 2 bid regimens were statistically significant, but the bid 10-day regimen was significantly more effective than the bid 5-day regimen in younger subjects. In the study population as a whole, results were similar to those in per protocol subjects. Overall the incidence of protocol-defined diarrhea was 26.7% (74 of 277) in the tid 10-day group, compared with 9.6% (27 of 280) in the bid 10-day group (P < 0.0001) and 8.7% (25 of 286) in the bid 5-day group (P < 0.0001). CONCLUSIONS: In comparison with the original formulation of Augmentin administered tid for 10 days in the treatment of AOM in children, the new formulation administered bid for 10 days provides at least equivalent efficacy and causes substantially less diarrhea. Administration for 5 days appears not to provide equivalent efficacy, but the difference appears limited to younger children and the margin of difference is small.

Acute Disease↗
PubMed1997

Study of use of cefdinir versus cephalexin for treatment of skin infections in pediatric patients. The Cefdinir Pediatric Skin Infection Study Group.

Three hundred ninety-four patients, aged 6 months to 12 years, entered a multicenter, randomized, controlled, investigator-blind study comparing cefdinir, 7 mg/kg of body weight twice a day, with cephalexin, 10 mg/kg four times a day, each given for 10 days. The most common infections treated were impetigo and secondary infection of preexisting dermatitis. The most common pathogens isolated were Staphylococcus aureus and Streptococcus pyogenes. Two hundred thirty-one patients were microbiologically evaluable. Microbiologic eradication rates were 164 of 165 pathogens (99.4%) in the cefdinir group and 152 of 156 pathogens (97.4%) in the cephalexin group (P = 0.14). Clinical cure rates were 116 of 118 patients (98.3%) in the cefdinir group and 106 of 113 patients (93.8%) in the cephalexin group (P = 0.056). Sixteen percent of cefdinir patients and 11% of cephalexin patients experienced adverse events (P = 0.11), the most common being diarrhea, which affected 8% of the cefdinir group and 4% of the cephalexin group. Cefdinir appears to be an effective and well-tolerated agent for the treatment of uncomplicated skin and skin structure infections in pediatric patients.

Cefdinir↗
PubMed1996

Chemokines and lymphocyte biology.

The past few years have seen significant growth in the number of known chemokines. Along with expansion in this field has come an appreciation of a role for chemokines beyond the chemotaxis of leukocytes. In particular, it appears that these molecules may represent major products of activated lymphocytes and that, in addition to chemotaxis, some of them may also regulate the growth, activation, and differentiation of lymphocytes.

Animals↗
PubMed1995

High prevalence of multidrug-resistant Streptococcus pneumoniae among children in a rural Kentucky community.

In 1992 drug-resistant Streptococcus pneumoniae was cultured with increasing frequency from aspirates of middle ear fluid from children with acute otitis media in a rural Kentucky community. To determine the prevalence of carriage of drug-resistant S. pneumoniae in the community, we obtained nasopharyngeal swabs from 158 (70%) of 227 children attending a child daycare center and from 82 children attending the county health center. S. pneumoniae was isolated from 126 children. Among 123 isolates tested 65 (53%) were penicillin-resistant, including 41 (33%) strains that were highly resistant; 61 (50%) were multidrug-resistant. Serotypes 19F, 6B, 23F and 6A comprised 89% of the penicillin-resistant isolates. Detection of a variety of serotypes and drug resistance patterns among nasopharyngeal isolates of S. pneumoniae suggests that multidrug-resistant pneumococcal strains are endemic in this community. Surveillance for drug-resistant pneumococci with the use of respiratory secretions obtained by nasopharyngeal swab may provide useful information on the prevalence of drug-resistant strains causing invasive disease and otitis media. Such information could be used to guide empiric therapy of pneumococcal infections.

Carrier State↗
PubMed1995

Penicillin-resistant Streptococcus pneumoniae in acute otitis media: risk factors, susceptibility patterns and antimicrobial management.

From January, 1992, to January, 1994, penicillin-resistant (minimal inhibition concentration (MIC) > 0.06 microgram/ml) Streptococcus pneumoniae (PRSP) isolates accounted for 48 (17%) of 283 isolates from acute otitis media (AOM) or recurrent AOM in 246 ambulatory patients in rural Kentucky. By broth microdilution, relatively penicillin-resistant (MIC > 0.06 to 1.0 microgram/ml) and highly penicillin-resistant (MIC > or = 2.0 micrograms/ml) strains were detected in 25 (16%) and 23 (15%), respectively, of 157 pneumococcal middle ear isolates. Using 1994 National Committee for Clinical Laboratory Standards breakpoints for pneumococci (unavailable for oral cephalosporins except cefuroxime), highly PRSP strains were almost uniformly susceptible to clindamycin and vancomycin. In contrast highly PRSP strains were resistant to most oral antimicrobials customarily used for AOM with one-third of strains highly resistant (MIC > or = 2.0 micrograms/ml) to ceftriaxone. Serotypes 6B, 19F and 23F accounted for 95% of highly PRSP strains and serotype 9V for 48% of relatively PRSP strains. By multivariate analysis, otitis-prone condition (P = 0.0008) and number of antibiotic courses before day of culture (P < 0.0001) were independently predictive of PRSP. Highly PRSP isolates were more commonly isolated from patients recently treated within 3 days (30%) vs. those who completed therapy more than 3 days earlier (2%) (P < 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗
PubMed1994

Characterization of a 70-kDa, EBV gp350/220-binding protein on HSB-2 T cells.

EBV binds and infects HSB-2 T cells via a receptor distinct from CD21. To further study this novel EBV receptor, we expressed the first 470 amino acids of the EBV-gp350/220 using the baculovirus expression system. The recombinant gp350/220(1-470) has a m.w. of 95 kDa, reacts with anti-gp350/220 Abs, and binds CD21 in ELISA. Radiolabeled gp350/220(1-470) binds both HSB-2 and Raji cells. The gp350/220(1-470) protein also inhibits EBV binding to both HSB-2 and Raji, detected by flow cytometry. Lysates of HSB-2 cells compete with CD21 for binding to gp350/220(1-470), suggesting that the two receptors bind related epitopes on the recombinant protein. Scatchard analysis reveals that gp350/220(1-470) binds to 34,000 high affinity sites/HSB-2 cell (Kd = 0.92 x 10(-8) M) compared with the 97,000 high affinity sites bound/Raji cell (Kd = 1.78 x 10(-8) M). Utilizing a gp350/220(1-470)-affinity matrix, we identify a 70-kDa (55-kDa nonreduced) protein on the surfaces of 125I-labeled HSB-2 cells. Binding of this protein to the matrix is inhibited by anti-gp350/220 Ab 72A1. In summary, we characterize a novel EBV-binding molecule on HSB-2 cells, compare its reactivity with gp350/220 to that of CD21, and provide evidence of a gp350/220-reactive, 70-kDa protein on the surfaces of HSB-2 cells. In view of previous evidence of HSB-2 infectivity by EBV, we propose that the 70 kDa protein represents the novel EBV receptor.

Animals↗
PubMed1994

CD1+ human thymocytes proliferate in response to superantigen staphylococcal enterotoxin B1.

Exposure of human thymocytes to superantigens results in the deletion of thymocytes expressing specific TCR-V beta genes. The factors that contribute to this deletion may relate to the inherent nature of the T cell at a given stage of development. In this paper, we demonstrate that CD1+ human cortical thymocytes are capable of proliferating in response to a bacterial superantigen (staphylococcal enterotoxin B (SEB)) in the presence of autologous CD2-/low thymic APCs. Phenotypic analysis of the responding populations revealed that the majority of the CD1+ cells were CD4+CD8low or CD8+CD4low cells. The response is triggered by low concentrations of SEB, requires the participation of the TCR and IL-2R molecules, and is inhibited by cyclosporin A. Thymocytes that express specific V beta genes are expanded, which results in an engagement profile that parallels that found in PBLs. Additionally, four V beta-chains that have not been reported previously are shown to engage SEB. Once stimulated, the thymocytes failed to respond to additional SEB; however, they could be induced to proliferative with IL-2, which suggests that these expanded populations had become anergic. These data represent the first demonstration of a human cortical thymocyte subpopulation that responds to superantigen by proliferation and subsequent anergy.

Antigens, CD↗