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Biomedical subjects

C L King

Publications and source records attributed to C L King.

At least 19 recordsLinked to original sources
PubMed2001

Schistosoma haematobium-induced urinary tract morbidity correlates with increased tumor necrosis factor-alpha and diminished interleukin-10 production.

This study examined the hypothesis that the nature of the host cellular immune response to schistosome ova is a risk factor for urinary tract morbidity in areas in which Schistosoma haematobium is endemic. S. haematobium-infected children and adolescents with bladder pathology assessed by ultrasonography had 54-fold greater tumor necrosis factor (TNF)-alpha production and a 120-fold greater ratio of TNF-alpha to interleukin (IL)-10 release by peripheral blood mononuclear cells in response to egg antigens, in comparison with control children and adolescents matched by age, sex, and infection severity. Mycobacterial antigens also stimulated 7-fold more TNF-alpha among subjects with bladder morbidity than in control subjects, which suggests an innate predisposition to enhanced TNF-alpha production. Levels of egg antigen-induced IL-4 and -5 and interferon-gamma were equivalent in subjects with and without bladder pathology. Thus, children and adolescents predisposed to increased TNF-alpha production to S. haematobium infection are more likely to develop an exaggerated granulomatous response to ova trapped in the bladder wall, with associated urinary tract pathology.

Adolescent↗
PubMed2001

Immunization with Haemophilus influenzae type b-CRM(197) conjugate vaccine elicits a mixed Th1 and Th2 CD(4+) T cell cytokine response that correlates with the isotype of antipolysaccharide antibody.

Haemophilus influenzae type b (Hib) capsular polysaccharide (PS) induces protective antibodies but is T independent and poorly immunogenic in infants. Conjugate vaccines of Hib PS linked to proteins, such as CRM(197), increase the PS antibody titer and elicit immunologic memory. To define the conjugate-induced memory T cell response, 19 adults were immunized with Hib-CRM(197), and antibody titers, carrier protein-specific CD4(+) T cell proliferation, and cytokine production were measured. Hib-CRM(197) induced PS and CRM(197) antibodies, vigorous T cell recall responses, and production of cytokines, including interleukin (IL)-2, IL-5, IL-10, and interferon-gamma. There was marked variability in PS antibody titer, despite consistent CRM(197)-specific recall responsiveness, which correlated with peak IgM and IgA PS antibody titers. Correlations were also found between IL-2 and IL-5 and IgA PS antibody levels. Hib-CRM(197) induced a rapid increase in CRM(197)-specific memory T cells and mixed Th1/Th2 cytokines, which may regulate the isotype and quantity of PS antibody.

Adult↗
PubMed2001

Transmission intensity determines lymphocyte responsiveness and cytokine bias in human lymphatic filariasis.

Humans living in areas where filariasis is endemic vary greatly in their exposure to mosquito-borne infective third-stage larvae (L3) of these parasitic helminths. Because the intensity of exposure to Ags affects T cell differentiation and susceptibility to parasitic infections in murine models, we compared T cell and cytokine responses in 97 residents of two villages in Papua New Guinea, where transmission intensity of Wuchereria bancrofti differed by 63-fold (37 vs 2355 L3 per person per year). Residents of the high transmission village had 4- to 11-fold lower proliferation and IFN-gamma responses to filarial Ags, nonparasite Ag, and PHA by PBMC compared with the low transmission village (p < 0.01) even when subjects were matched for intensity of infection. In contrast, filarial Ag-driven IL-5 production was 5.5-fold greater (p < 0.001), and plasma IL-4 and TGF-beta levels were 4-fold and 34% higher, respectively, in residents of the high transmission village. IL-4 and IL-10 responses by PBMC differed little according to village, and increased production of the counterregulatory cytokines IL-10 or TGF-beta by PBMC did not correlate with weak proliferation and IFN-gamma responses. Plasma IL-5, IFN-gamma, and IL-10 levels were similar in the two villages. These data demonstrate that the intensity of exposure to L3 affects lymphocyte responsiveness and cytokine bias possibly by a mechanism that alters APC function.

Adolescent↗
PubMed2001

Inhibitory and enhancing effects of IFN-gamma and IL-4 on SHIV(KU) replication in rhesus macaque macrophages: correlation between Th2 cytokines and productive infection in tissue macrophages during late-stage infection.

HIV-1 is dual-tropic for CD4+ T lymphocytes and macrophages, but virus production in the macrophages becomes manifest only during late-stage infection, after CD4+ T cell functions are lost, and when opportunistic pathogens begin to flourish. In this study, the SHIV/macaque model of HIV pathogenesis was used to assess the role of cytokines in regulating virus replication in the two cell types. We injected complete Freund's adjuvant (CFA) intradermally into SHIV(KU)-infected macaques, and infused Schistosoma mansoni eggs into the liver and lungs of others. Tissues examined from these animals demonstrated that macrophages induced by CFA did not support viral replication while those induced by S. mansoni eggs had evidence of productive infection. RT-PCR analysis showed that both Th1 (IL-2 and IFN-gamma) and Th2 cytokines (IL-4 and IL-10) were present in the CFA lesions but only the Th2 cytokines were found in the S. mansoni lesions. Follow-up studies in macaque cell cultures showed that whereas IFN-gamma caused enhancement of virus replication in CD4+ T cells, it curtailed viral replication in infected macrophages. In contrast, IL-4 enhanced viral replication in infected macrophages. These studies strongly suggest that cytokines regulate the sequential phases of HIV replication in CD4 T cells and macrophages.

Animals↗
PubMed2001

Malignant glioma cells use MHC class II transactivator (CIITA) promoters III and IV to direct IFN-gamma-inducible CIITA expression and can function as nonprofessional antigen presenting cells in endocytic processing and CD4(+) T-cell activation.

Malignant gliomas (MGs), lethal human central nervous system (CNS) neoplasms, contain tumor infiltrating lymphocytes (TIL). Although MHC class II molecules are frequently detected on MG cells, suggesting that they may be capable of antigen (Ag) presentation to CD4(+) T cells, deficiencies in CD4(+) T-cell activation are associated with these nonimmunogenic tumors. We evaluated regulation of the MHC class II transactivator (CIITA), the key intermediate that controls class II expression, in MG cells and tested whether MG cells could process native Ag. After interferon-gamma (IFN-gamma) stimulation, MG cells upregulated CIITA and class II molecules. IFN-gamma-inducible CIITA expression in MG cells, as well as primary human astrocytes, was directed by two CIITA promoters, pIV, the promoter for IFN-gamma-inducible CIITA expression in nonprofessional antigen-presenting cells (APC), and pIII, the promoter that directs constitutive CIITA expression in B cells. Both pIII and pIV directed CIITA transcription in vivo in MGs and ex vivo in IFN-gamma-activated primary MG cultures. We also demonstrate for the first time that MG cells can process native Ag for presentation to CD4(+) MHC class II-restricted Th1 cells, indicating that MG cells can serve as nonprofessional APC. CIITA may be a key target to modulate MHC class II expression, which could augment immunogenicity, Ag presentation, and CD4(+) T-cell activation in MG therapy.

Adult↗
PubMed2001

Transmission intensity and human immune responses to lymphatic filariasis.

Our understanding of how the host immune response influences the risk of developing disease has changed dramatically over the past decade. Previously, the spectrum of disease associated with lymphatic filariasis was largely attributed to the nature of the host immune response. Now, we appreciate that the duration and intensity of infection and possibly the direct influence of parasite-derived molecules also determine the risk of disease. Individuals chronically infected with lymphatic filariasis generally have an impaired lymphocyte proliferation response to filarial antigens and favour Th2-type cytokine responses. This ability to down-modulate the host immune response may help protect the host from disease. Defects in antigen-presenting cell (APC) function appear to participate in this acquired immune hyporesponsiveness, although the mechanisms as to how this occurs are poorly understood. Here, we present evidence that repeated exposure to infective stage larvae and their secreted products may stimulate basophils and mast cells to related products that may impair APC function.

Animals↗
PubMed2001

Murine schistosomiasis mansoni: coordinate cytokine regulation and differences in cellular immune responses of granuloma cells and splenocytes to endogenous and exogenous schistosome egg antigens.

To better understand the cellular immune mechanisms that regulate granulomatous inflammation to Schistosoma mansoni ova, we examined the dynamics of lymphocyte proliferation and cytokine expression by granuloma cells and splenocytes to endogenous and exogenous schistosome egg antigen (SEA) 6-19 weeks postinfection. Compared to splenocytes, granuloma cells (partially CD4+ cells) which are at the site of antigen release were highly activated by endogenous SEA and terminally differentiated as indicated by the more than 10-fold greater frequency of ex vivo interleukin (IL)-4, IL-5 and interferon (IFN)-gamma -secreting cells, greater levels of constitutive cytokine production and failure to proliferate to either endogenous or exogenous SEA. Endogenous cytokine production by granuloma cells was coordinately regulated, enhanced little by exogenous SEA, and temporally correlated with granulomatous inflammation. By contrast, CD4+ splenocytes produced comparatively little cytokine release by endogenous antigen, whereas exogenous SEA strongly induced IL-4, IL-5, IL-10 and IFN-gamma production and lymphocyte proliferation that correlated poorly with the dynamics of granulomatous inflammation. These results show that cytokine responses to endogenous SEA correlated better with granulomatous inflammation than responses to exogenous SEA. Furthermore, granuloma cells and splenocytes demonstrated strikingly different proliferative responses and dynamics of cytokine expression, suggesting that how SEA reactive lymphocytes traffic between lymphoid tissues and the granuloma is critical to a better understanding of the mechanisms of granulomatous inflammation and its modulation.

Animals↗
PubMed2001

An overview of animal models in experimental schistosomiasis and refinements in the use of non-human primates.

The complex nature of the schistosome parasite and its interaction with the mammalian host necessitates the continued use of live intact animal models in schistosomiasis research. This review acknowledges this necessity and highlights some of the important insights into the pathogenesis of the disease that have been gained from using various animal models. The use of non-human primates as more relevant models of human schistosomiasis is stated. In addition, the importance of animal welfare consideration when using primates for research is emphasized. Finally, some guidelines for the refined capture, handling and early humane endpoints for non-human primates to be used in experimental schistosomiasis are suggested.

Animal Welfare↗
PubMed2000

Frequent umbilical cord-blood and maternal-blood infections with Plasmodium falciparum, P. malariae, and P. ovale in Kenya.

The prevalence of malaria infection in 102 paired maternal-blood and umbilical cord-blood samples was assessed by microscopy and polymerase chain reaction (PCR) in a holoendemic area in Kenya. Plasmodium falciparum single-species infection was detected in maternal peripheral blood (3.4%), whereas microscopy indicated that no Plasmodium species were in cord blood. In contrast, maternal-blood samples showed a PCR prevalence of 48% for P. falciparum, 25% for P. malariae, and 24% for P. ovale, and cord-blood samples showed a PCR prevalence of 32%, 23%, and 21%, respectively. Although mothers with mixed-species infections were more likely to have offspring infected with mixed species, the specific malaria species were discordant in paired maternal- and cord-blood samples. Triple-species infections were observed in 11 cord- and maternal-blood samples at a 5.5-fold greater frequency than expected. These findings indicate that Plasmodium species infections in cord blood are common, occur at lower densities, and may be acquired before parturition.

Adolescent↗
PubMed2000

Repeated exposure induces periportal fibrosis in Schistosoma mansoni-infected baboons: role of TGF-beta and IL-4.

Recently, we observed that repeated Schistosoma mansoni infection and treatment boost Th2-associated cytokines and TGF-beta production in baboons. Other studies have shown that some chronically infected baboons develop hepatic fibrosis. Because TGF-beta, IL-2, and IL-4 have been shown to participate in development of fibrosis in murine schistosomiasis, the present study examined whether repeated exposure stimulates hepatic fibrosis in olive baboons. To test this hypothesis, animals were exposed to similar numbers of S. mansoni cercariae given once or repeatedly. After 19 wk of infection, animals were cured with praziquantel and reinfected once or multiple times. Hepatic granulomatous inflammation and fibrosis were assessed from serial liver biopsies taken at weeks 6, 9, and 16 after reinfection and egg Ag (schistosome egg Ag)-specific cytokine production by PBMC were measured simultaneously. Periportal fibroblast infiltration and extracellular matrix deposition (fibrosis), angiogenesis, and biliary duct hyperplasia developed in some animals. The presence and amount of fibrosis directly correlated with the frequency of exposure. Fibrosis was not associated with adult worm or tissue egg burden. The amount of fibrosis correlated with increased schistosome egg Ag-driven TGF-beta at 6, 9, and 16 wk postinfection (rs = 0.9, 0.8, and 0.54, respectively, all p < 0.01) and IL-4 production (p = 0.02) at 16 wk postinfection and not IFN-gamma, IL-2, IL-5, or IL-10. These data suggest that repeated exposure is a risk factor for periportal fibrosis by a mechanism that primes lymphocytes to produce increased levels of profibrotic molecules that include TGF-beta and IL-4.

Animals↗
PubMed2000

IFN-gamma is necessary but not sufficient for anti-CD40 antibody-mediated inhibition of the Th2 response to Schistosoma mansoni eggs.

The injection of Schistosoma mansoni eggs into the footpads of mice results in a localized Th2 cytokine response and tissue eosinophilia. We examined whether treatment with CD40-activating Abs would block the development of Th2 cytokine responses and eosinophilic tissue pathology in this model. Seven days after C57BL/6 mice were injected with eggs and the FGK45 anti-CD40 Ab, Ag-specific synthesis of IL-4, IL-5, and IL-13 in lymph node culture was reduced (>10-fold) relative to control mice treated with eggs and rat IgG. In contrast, IFN-gamma and IL-12 were increased in both culture supernatants and in the serum. Similar changes in lymph node cytokine mRNA were observed in vivo, and tissue eosinophilia was reduced nearly 20-fold. Th2 cytokine responses in anti-CD40-treated IFN-gamma-/- and IL-12 p40-/- C57BL/6 mice were unaffected, although anti-CD40 induced high levels of systemic and local IFN-gamma production in both wild-type and IL-12 p40-/- mice. We conclude that CD40-activating treatments strongly reverse the immune phenotype generated in response to a classic, Th2-biasing stimulus and stimulate IFN-gamma through a novel IL-12-independent pathway. This model for Th1-deviating immune therapy may have relevance to the treatment of Th2-dependent diseases in general.

Animals↗
PubMed2000

The erythrocyte binding motif of plasmodium vivax duffy binding protein is highly polymorphic and functionally conserved in isolates from Papua New Guinea.

The Duffy binding protein (DBP) of Plasmodium vivax is a critical adhesion ligand that participates in merozoite invasion of human Duffy positive reticulocytes. Binding domains have been shown to lie within a conserved N-terminal cyteine-rich region, region II, that contains 330-aa and the critical binding residues have been recently mapped to 170-aa stretch within this region. Previous studies on few isolates indicated a significant degree of polymorphism in region II (DBPII). To examine further the degree of variability of DBPII, and whether these variants produce functional changes, DBPII was amplified by nested PCR from 24 isolates from Papua New Guinea, and the amplicons were cloned and sequenced. One synonymous and 18 non-synonymous mutations were identified. Altogether, 93% of the cumulative polymorphisms lie within the 170-aa region. Targeted surface expression of region II of two different alleles on the surface of Cos7 cells did not affect their binding to Duffy positive erythrocytes. These results indicate that polymorphisms in the critical binding motifs do not alter its function. If DBPII variation arose to avert mechanisms of protective immunity targeting the DBP, vaccine development employing the parasite binding ligand may require strategies to minimize the effect of this polymorphism.

Adult↗
PubMed2000

Influence of age and HLA type on interferon-gamma (IFN-gamma) responses to a naturally occurring polymorphic epitope of Plasmodium falciparum liver stage antigen-1 (LSA-1).

Antigenic polymorphism and HLA restriction may limit the immunogenicity of a subunit vaccine against liver-stage Plasmodium falciparum. We examined 59 clinical isolates and five laboratory clones of P. falciparum for polymorphism in the N- and C-terminal regions of LSA-1, evaluated binding of the corresponding peptides to selected HLA class I alleles, and measured IFN-gamma responses in residents of a malaria-endemic area of Papua New Guinea where HLA-A*1101, -24, -B13, and -B40 are the most common class I alleles. LSA-1 polymorphism was limited to a single non-synonymous mutation encoding serine (S), proline (P), or threonine (T) at amino acid 85. Nine-mer 84-92 peptides with S, T, or P at the primary anchor position bound differentially to HLA-A11, -A2, and -B7. IFN-gamma ELISPOT responses increased with age in malaria-exposed subjects: 14-16% and 30-36% of 2-5- and 6-54-year-olds, respectively, had > or =10 IFN-gamma-secreting cells/106 peripheral blood mononuclear cells when stimulated with at least one peptide variant (P<0.05). IFN-gamma responses to all three peptides were also greater for older than younger individuals. No children < 3 years old had lymphocytes that responded to all three 84-92 peptides, whereas 45% of adults (mean age 48 years) had aggregated IFN-gamma responses. These data support the notion that age-related cumulative exposure to P. falciparum increases the frequency of IFN-gamma responses to polymorphic epitopes of liver-stage antigens such as LSA-1.

Adolescent↗
PubMed2000

Hepatic granulomatous response to Schistosoma mansoni eggs in BALB/c mice and olive baboons (Papio cynocephalus anubis).

Hepatic granulomatous inflammation is one of the key pathological lesions of a patent Schistosoma mansoni infection. This study was concerned with the sequential induction, formation and eventual modulation of the schistosome egg granuloma in the mouse, which develops schistosome-induced hepatic fibrosis, and the olive baboon, which usually does not. Six baboons were each infected with 1500 S. mansoni cercariae and liver biopsies were collected at weeks 6, 9, 13 and 17 post-infection (p.i.). The mice (n=25) were each infected with 100 cercariae and killed in groups of five at weeks 6, 9, 12, 18 and 21 p.i. Peak granuloma size was observed at week 6 p.i. in baboons (mean 355 +/- 65.6 microm) but at week 12 p.i. in mice (299 +/- 40.5 microm). Eosinophils were more abundant in the baboon (60.6 +/- 8.9%) than in the mouse (41.2 +/- 8.4%) at the time of maximal granuloma size (P < 0.01). Neutrophils formed 21.1 +/- 6.3% of peak mouse granulomata but were virtually absent in baboon granulomata. A feature of the modulating baboon granulomata was the emergence of multinucleated giant cells (MGCs); modulating mouse granulomata, on the other hand, were characterized by infiltration of fibroblasts and collagen deposition. Thus, by week 21 p.i. mouse granulomata were 92 +/- 16.0 microm in diameter and well delineated by concentric layers of fibrous tissue. Granulomata, however, were present in only two of the baboons at week 17 p.i. (44 +/- 61.2 microm in diameter). The other four had peri-portal cellular infiltration without granuloma formation, implying that baboon granulomata resolve spontaneously. These data suggest that high tissue eosinophilia and MGC formation are particularly efficient in bringing about the destruction of schistosome eggs and subsequent resolution of the egg granuloma without fibrosis. In conclusion, the baboon model more closely mimics the pathogenesis observed in man than does the mouse model.

Acute Disease↗
PubMed2000

Cytokine responses to Plasmodium falciparum liver-stage antigen 1 vary in rainy and dry seasons in highland Kenya.

Seasonal epidemics of malaria occur in highland areas of western Kenya where transmission intensity varies according to rainfall. This study describes the seasonal changes in cytokine responses to Plasmodium falciparum liver-stage antigen 1 (LSA-1) by children (< or =17 years old) and adults (> or =18 years old) living in such a highland area. Fourteen- to 24-mer peptides corresponding to the N- and C-terminal nonrepeat regions of LSA-1 stimulated production of interleukin-5 (IL-5), interleukin-10 (IL-10), gamma interferon (IFN-gamma), and tumor necrosis factor alpha (TNF-alpha) by peripheral blood mononuclear cells (PBMC) from 17 to 73% of individuals in both age groups in both seasons. IL-10 and TNF-alpha responses were more frequent during the high-transmission, rainy season than during the low-transmission, dry season (73 and 67% versus 17 and 25% response rates, respectively). In contrast, there was no seasonal change in the proportion of LSA-1-driven IFN-gamma and IL-5 responses. Children produced less IFN-gamma than adults, but IL-5, IL-10, and TNF-alpha levels were similar for both age groups. Depletion of CD8(+) cells from PBMC decreased IFN-gamma but increased IL-10 production. Individuals with LSA-1-stimulated IL-10 responses in the dry season were less likely to become reinfected in the subsequent rainy season than those without IL-10 responses (25% versus 49%; P = 0.083). These data support the notion that maintenance of LSA-1-driven IL-10 and TNF-alpha responses requires repeated and sustained exposure to liver-stage P. falciparum. In contrast, IFN-gamma responses increase slowly with age but persist once acquired. CD8(+) T cells are the major source of IFN-gamma but may suppress production or secretion of IL-10.

Adolescent↗
PubMed1999

Helminth- and Bacillus Calmette-Guérin-induced immunity in children sensitized in utero to filariasis and schistosomiasis.

Infants and children are routinely vaccinated with bacillus Calmette-Guérin (BCG) in areas of the world where worm infections are common. Because maternal helminth infection during pregnancy can sensitize the developing fetus, we studied whether this prenatal immunity persists in childhood and modifies the immune response to BCG. Children and newborns living in rural Kenya, where BCG is administered at birth and filariasis and schistosomiasis are endemic, were examined. T cells from 2- to 10-year-old children of mothers without filariasis or schistosomiasis produced 10-fold more IFN-gamma in response to mycobacterial purified protein derivative than children of helminth-infected mothers (p < 0.01). This relationship was restricted to purified protein derivative because maternal infection status did not correlate with filarial Ag-driven IL-2, IFN-gamma, IL-4, or IL-5 responses by children. Prospective studies initiated at birth showed that helminth-specific T cell immunity acquired in utero is maintained until at least 10-14 mo of age in the absence of infection with either Wuchereria bancrofti or Schistosoma haematobium. Purified protein derivative-driven T cell IFN-gamma production evaluated 10-14 mo after BCG vaccination was 26-fold higher for infants who were not sensitized to filariae or schistosomes in utero relative to subjects who experienced prenatal sensitization (p < 0.01). These data indicate that helminth-specific immune responses acquired during gestation persist into childhood and that this prenatal sensitization biases T cell immunity induced by BCG vaccination away from type 1 IFN-gamma responses associated with protection against mycobacterial infection.

Adolescent↗
PubMed1999

Increased levels of soluble interleukin-4 receptor in the sera of patients with visceral leishmaniasis.

Kenyan subjects with visceral leishmaniasis were examined for evidence of increased production of soluble interleukin-4 receptor (sIL-4R). Soluble IL-4R regulates the bioactivity of IL-4, a cytokine important in mediating progressive forms of leishmaniasis. Persons with visceral leishmaniasis sustained 8- to 10-fold more circulating sIL-4R compared with Papua New Guinea residents with documented filariasis or uninfected Kenyan and North American subjects. Soluble IL-2R concentrations were elevated nonspecifically in both visceral leishmaniasis and filariasis patients. These findings are significant given that IL-4 induces sIL-4R in mice, and treatment with recombinant sIL-4R cures progressive murine leishmaniasis dependent on IL-4 bioactivity. Further studies are indicated to determine whether the immunologic detection of IL-4 produced in human visceral leishmaniasis is obscured because of sequestration by soluble receptor and whether the production of sIL-4R is relevant to the pathogenesis of visceral leishmaniasis.

Animals↗