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Biomedical subjects

M F Good

Publications and source records attributed to M F Good.

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

Is an epitope on keratin 17 a major target for autoreactive T lymphocytes in psoriasis?

Psoriasis is a T cell-mediated inflammatory skin disease that has been associated with infections by group A beta-haemolytic streptococci. In a previous study of patients with active psoriasis we demonstrated an increased frequency of circulating Th1-like cells that responded to 20 amino acid (aa) streptococcal M-peptides sharing sequences with human keratin. These cells disappeared after ultraviolet B (UVB)-induced clinical remission. Using T cells from the blood of 17 psoriatic patients and 17 healthy controls we have now compared the numbers of interferon-gamma (IFN-gamma)-producing cells induced by seven 18-20 aa keratin peptides and five corresponding M-peptides. The most frequent and strongest responses were observed to a peptide from keratin 17 that shares ALEEAN sequence with M-protein. The responses to this peptide were stronger than to the corresponding M-peptide containing the ALEEAN sequence. After UVB treatment T cell responses to all the M- and keratin peptides were abolished, while responses to the positive control antigen streptokinase/streptodornase (SK/SD) were not affected. These findings are consistent with the notion that aa sequences which keratin has in common with M-protein may be a major target for autoreactive T cells in psoriasis.

Amino Acid Sequence↗
PubMed1999

Malaria parasite-specific Th1-like T cells simultaneously reduce parasitemia and promote disease.

CD4+ T cells have been implicated in immunity to the blood stages of malaria and cytokines associated with both monocyte and T cell activation have been implicated in disease. To determine whether specific T cells capable of inhibiting parasite growth can also mediate pathology we have transfused populations of Plasmodium berghei-specific T cells into normal and immunodeficient naive mice. We observed that they could inhibit parasite growth but were unable to save the animals which exhibited significantly greater anaemia and weight loss than control infected animals receiving either no T cells or T cells specific for ovalbumin. T cell-dependent tomour necrosis factor (TNF)alpha was a critical component in both parasite killing and disease promotion. Experiments with blocking antibodies demonstrated that all T-cell mediated antiparasitic immunity and all T-cell mediated weight loss was TNF-dependent. Blocking TNF-alpha in mice that received parasite-specific T cells prolonged the survival of the mice. Nitric oxide demonstrated no antiparasite effect, but was involved in the regulation of T-cell mediated weight loss. The data thus show that while parasite-specific CD4+ T cells can significantly limit parasite growth, such an effect need not be beneficial to the host, and that TNF-alpha and nitric oxide are critical effector molecules operating downstream of parasite-specific T cells in both immunity and disease.

Animals↗
PubMed1999

Functional analysis of IgA antibodies specific for a conserved epitope within the M protein of group A streptococci from Australian Aboriginal endemic communities.

The mucosa is one of the initial sites of group A streptococcal (GAS) infection and salivary IgA (sIgA) is thought to be critical to immunity. However, the target epitopes of sIgA and the function of sIgA in GAS immunity, in particular the role of accessory cells and complement, is largely unknown. We studied the aquisition and the function of sIgA specific for a conserved region epitope, p145 (sequence: LRRDLDASREAKKQVEKALE) of the M protein. Peptide 145-specific sIgA is highly prevalent within an Aboriginal population living in an area endemic for GAS and acquisition of p145-specific sIgA increases with age, consistent with a role for such antibodies in immunity to GAS. Human sIgA and IgG specific for p145 were affinity purified and shown to opsonize M5 GAS in vitro. Opsonization could be specifically inhibited by the addition of free p145 to the antibodies during assay. Opsonization of GAS was totally dependent on the presence of both complement and polymorphonuclear leukocytes, and, moreover, affinity-purified p145-specific sIgA was shown to fix complement in the presence of M5 GAS. These data show that mucosal IgA to this conserved region peptide within the M protein has an important role in human immunity against GAS and may be useful in a broad-based cross-protective anti-streptococcal vaccine.

Adolescent↗
PubMed1998

Deletion of Plasmodium berghei-specific CD4+ T cells adoptively transferred into recipient mice after challenge with homologous parasite.

The immune response to malaria parasites includes T cell responses that reduce parasites by effector T cell responses and by providing help for antibody responses. Some parasites are more sensitive to antibody and others are more sensitive to cell-mediated immunity. We demonstrate that cultured CD4(+) T cells that produce interferon gamma and interleukin 2, but not interleukin 4, in response to stimulation with the rodent parasite Plasmodium berghei can reduce but not eliminate parasites in vivo after adoptive transfer. Although cells can persist in vivo for up to 9 months in uninfected mice, infection results in elimination of up to 99% of specific T cells in different tissues, as judged by tracking T cells labeled with the fluorescent dye 5-(and -6)-carboxyfluorescein diacetate succinimidyl ester. T cells specific for ovalbumin are unaffected. In vivo activation and division of transferred T cells per se are not responsible for deletion because T cells positive for 5-(and -6)-carboxyfluorescein diacetate succinimidyl ester divide up to six times within 7 days in uninfected mice and are not deleted. Understanding the factors responsible for parasite-mediated specific deletion of T cells would enhance our knowledge of parasite immunity.

Adoptive Transfer↗
PubMed1998

Vaccine-induced cytotoxic T lymphocytes protect against retroviral challenge.

The development of prophylactic vaccines against retroviral diseases has been impeded by the lack of obvious immune correlates for protection. Cytotoxic T-lymphocyte (CTL), CD4-lymphocyteS, chemokine and/or antibody responses have all been associated with protection against HIV and AIDS; however, effective and safe vaccination strategies remain elusive. Here we show that vaccination with a minimal ovine CTL peptide epitope identified within gp51 of the retrovirus bovine leukemia virus (BLV), consistently induced peptide-specific CTLs. Only sheep whose CTLs were also capable of recognizing retrovirus-infected cells were fully protected when challenged with BLV. This retrovirus displays limited sequence variation; thus, in the relative absence of confounding CTL escape variants, virus-specific CTLs targeting a single epitope were able to prevent the establishment of a latent retroviral infection.

Animals↗
PubMed1998

Human and murine T-cell responses to allelic forms of a malaria circumsporozoite protein epitope support a polyvalent vaccine strategy.

Mouse models and a recent vaccine trial have indicated the importance of T-cell immunity to the circumsporozoite protein (CSP) of malaria sporozoites. One of the major impediments for the development of a CSP-based vaccine is that human T-cell epitopes, identified on the CSP, span regions of significant point mutational polymorphism. Studies with human and mouse T-cell clones have indicated that this polymorphism affects T-cell cross-reactivity to Th2R and Th3R, the two most polymorphic and immunodominant epitopes. We extend this observation with polyclonal human T-cell lines, from 11 donors, raised to known variants of Th2R. These lines showed limited but variable cross-reactivity with the heterologous peptides. T cells from B10.A4(R) (I-Ak) mice immunized with each of 18 natural variants of Th2R indicated a similar, limited, cross-reactivity. I-Ak competition assays showed that a number of peptides were unable to bind because of a single polymorphic residue. In both the human and mouse assays, analysis of the sequences of immunogenic cross-reactive and non-cross-reactive peptides suggested that the individual polymorphic residues affect the three-dimensional conformation of the peptide within the major histocompatibility complex (MHC) groove in an, as yet, unpredictable way. These observations argue that design of an epitope able to generate broad cross-reactivity is, to date, not possible. However, despite the limited cross-reactivity of the individual human T-cell lines, most of the donors had T-cell repertoires capable of recognizing all or nearly all of the variants tested, which supports a strategy using a multivalent vaccine.

Alleles↗
PubMed1998

Definition of T cell epitopes within the 19 kDa carboxylterminal fragment of Plasmodium yoelii merozoite surface protein 1 (MSP1(19)) and their role in immunity to malaria.

MSP1(19) is one of the leading malaria vaccine candidates. However, the mechanism of protection is not clear. To determine whether MSP1(19)-specific effector T cells can control parasitaemia, we analysed the specificity of T cells induced following immunization with recombinant forms of P. yoelii MSP1(19) and asked whether they could protect mice. There was no evidence that effector T cells were capable of protecting since: (1) immunization of mice with yMSP1(19), but not defined epitopes, was able to induce protection; and (2) long term MSP1(19)-specific CD4+ T cell lines were incapable of adoptively transferring protection. In contrast, priming mice with the T cell epitopes resulted in a rapid anamnestic antibody response to MSP1(19) after either challenge with MSP1(19) or parasite. Thus, MSP1(19) contains multiple T cell epitopes but such epitopes are the targets of helper T cells for antibody response but not of identified effector T cells capable of controlling parasitaemia.

Adoptive Transfer↗
PubMed1998

Intranasal immunization with yeast-expressed 19 kD carboxyl-terminal fragment of Plasmodium yoelii merozoite surface protein-1 (yMSP119) induces protective immunity to blood stage malaria infection in mice.

Variable protection against malaria blood-stage infection has been demonstrated in mice following parenteral immunization with the highly conserved 19 kD carboxylterminal fragment of the merozoite surface protein-1 (MSP119) using CFA/IFA and other adjuvants. Here we show that intranasal immunization of BALB/C mice with yeast expressed Plasmodium yoelii MSP119 plus a mixture of native and recombinant cholera toxin B subunit, could induce serum MSP119-specific antibodies at titres ranging from 20 000 to 2 560 000. The Ig subclass responses were predominantly G1 and G2b. Intranasal immunization led to protection following challenge (peak parasitaemia < 1%) in mice with the highest MSP119-specific titre (>/= 640 000). In two of the three protected mice, a peak parasitaemia of 0.1%-1% was followed by a boost of the antibody response whereas one of the three protected mice did not boost its antibody response after a peak parasitaemia of 0.02%. In unprotected mice, antibody levels rose, then fell, following the detection of parasites in the peripheral blood. CD4+ T cell-depletion abrogated the ability of the mice to boost their antibody response following challenge. These data demonstrate the potential for intranasal immunization with MSP119 to protect against malaria.

Adjuvants, Immunologic↗
PubMed1998

Pathways and strategies for developing a malaria blood-stage vaccine.

In the past 10 years, our knowledge of the malaria parasite has increased enormously: identification and analysis of parasite antigens, demonstration of protection of monkeys and mice following immunization with these antigens, and better understanding of the mechanisms of immunity to malaria and the pathogenesis of disease in malaria. Powerful new adjuvants have been developed, some of which--it is hoped--will be suitable for human use. Recently, a successful human trial of a vaccine aimed at sporozoites (the stage inoculated by mosquitoes) was completed. However, it is the red blood cell stage of the parasite that causes disease, and it is against this stage--in which the parasite grows at an exponential rate--that it has proven very difficult to induce a protective immune response by vaccination. This review focuses on recent exciting developments toward a blood-stage vaccine. We analyze the major obstacles to vaccine development and outline a strategy involving public- and industry-funded research that should result in development of a vaccine.

Animals↗
PubMed1997

A cryptic T cell epitope on the apical membrane antigen 1 of Plasmodium chabaudi adami can prime for an anamnestic antibody response: implications for malaria vaccine design.

We have investigated the proliferative and Th cell responses to the Plasmodium chabaudi adami DS homologue of the Plasmodium falciparum apical membrane Ag 1 (AMA-1), a leading malaria vaccine candidate. Immunodominant T cell epitopes were defined following immunization of BALB/c mice with Escherichia coli-expressed, refolded P. c. adami DS AMA-1 recombinant protein and testing cells from the draining lymph nodes for responses against a series of overlapping peptides spanning P. c. adami AMA-1. A limited number of major T cell sites were identified in both conserved and variable regions of the protein. Several cryptic epitopes that evoked T cell responses following immunization with peptides, but not after protein immunization, were also identified. Adoptive transfer of a T cell line specific for a conserved cryptic epitope (corresponding to residues 31-50) provided help for an anti-AMA-1 protein-specific Ab response following in vivo challenge with P. c. adami parasitized RBC, such that AMA-1-specific Abs appeared more rapidly in recipient mice than in controls. Furthermore, T cells specific for cryptic epitopes afforded partial protection against P. c. adami infection in nude mice. The identification of conserved cryptic Th cell epitopes has important implications for malaria vaccine design.

Adoptive Transfer↗
PubMed1997

Complete protective immunity induced in mice by immunization with the 19-kilodalton carboxyl-terminal fragment of the merozoite surface protein-1 (MSP1[19]) of Plasmodium yoelii expressed in Saccharomyces cerevisiae: correlation of protection with antigen-specific antibody titer, but not with effector CD4+ T cells.

The 19-kDa carboxyl-terminal fragment of the merozoite surface protein-1 (MSP1) is a leading malaria vaccine candidate but is unable to induce immunity in all monkeys or all strains of mice. The mechanism of immunity is unclear, although data show that cell-mediated immunity plays a critical role following immunization with the larger mature MSP1 protein. We optimized a vaccine protocol using the MSP1(19) fragment of Plasmodium yoelii expressed in Saccharomyces cerevisiae, such that following exposure of mice to parasites, they remained undetectable in peripheral blood, whereas control animals all died at very high parasitemia within 10 days. We then depleted the vaccinated mice of >99% of CD4+ T cells by anti-CD4 mAb treatment and could show that infections in most animals remained subpatent following challenge. Furthermore, mice in which the gene for the mu-chain of Ig had been disrupted could not be immunized with MSP1(19). Immunity in normal mice did not depend on the presence of an intact spleen nor production of nitric oxide, persisting unabated when >70% of splenic macrophages were depleted. Thus, while effector CD4+ T cells may contribute to immunity, neither they nor factors associated with a Th1-type cell mediated immune response appeared to play the major role in MSP1(19)-induced protection in normal mice. Furthermore, T cells were not sufficient for immunity in mice lacking B cells. In normal mice, protection correlated with a very high titer of MSP1(19)-specific Abs (>6,400,000), predominantly G1 and G2b, which may function by merozoite neutralization.

Animals↗
PubMed1997

Fine epitope specificity of antibodies to region II of the Plasmodium vivax circumsporozoite protein correlates with ability to bind recombinant protein and sporozoites.

Recent work has suggested that important B- and T-cell epitopes on the circumsporozoite protein (CSP) of Plasmodium vivax lie external to the major repeat regions of the protein. We have studied two naturally exposed human populations (Caucasian and Papua New Guineans) and determined the antibody response to yeast-derived recombinant CSPs, overlapping synthetic peptides spanning amino acids 76 348 of the Belem P. vivax CSP and overlapping peptides representing the variant repeats of the VK247 strain of P. vivax. We have demonstrated that the P. vivax CSP-specific antibody response is directed towards areas within the repeat region as well as areas external to this; but the dominant epitopes recognized by the two populations studied, were distinct. One epitope, lying external to the repeats and recognized by both populations, partially overlaps an area of the protein referred to as region II-plus. Sera from malaria-exposed Papua New Guineans and Thais contained antibodies to this epitope (V22, single letter amino acid sequence TCGVGVRVRRRVNAANKKPE) which were capable of recognizing sporozoites, as determined by quantitative inhibition IFA. Seventeen percent of PNG sera had antibodies to this peptide compared with 33% who had antibodies to the central repeats of the protein. Immunization of mice with recombinant CSP did not induce antibodies to V22. However, immunization with overlapping peptide epitopes representing this region (V21 or V22) induced specific antibodies but only two sera recognized both V21 and V22 and, by inference, the overlapping peptide sequence (TCGVGVRVRR). Antibodies in these two sera could bind recombinant CSP in ELISA; however, in contrast, nine sera which recognized either V21 or V22 alone did not bind CSP. Only one of two sera containing antibodies recognizing CSP stained P. vivax sporozoites. This serum also recognized an epitope dependent upon two amino acids aminoterminal to V22. These data suggest that the fine specificity of antibodies is a critical determinant for binding to both recCSP and sporozoites.

Adult↗
PubMed1997

A case report: immune responses and clinical course of the first human use of granulocyte/macrophage-colony-stimulating-factor-transduced autologous melanoma cells for immunotherapy.

The first use of granulocyte/macrophage-colony-stimulating-factor-transduced, lethally irradiated, autologous melanoma cells as a therapeutic vaccine in a patient, with rapidly progressive, widely disseminated malignant melanoma resulted in the generation of a novel antitumour immune response associated with partial, albeit temporary, clinical benefit. An initially negative reaction to non-transduced, autologous melanoma cells was converted to a delayed-type hypersensitivity (DTH) reaction of increasing magnitude following successive vaccinations. While intradermal vaccine sites showed prominent dendritic cell accrual, DTH sites revealed a striking influx of eosinophils in addition to activated/memory T lymphocytes and macrophages, recalling the histology of challenge tumour cell rejection in immune mice. Cytotoxic T lymphocytes (CTL) reactive with autologous melanoma cells were detectable at high frequency after vaccination, not only in limiting-dilution analysis, but also in bulk culture without added cytokines. Clonal analysis of CTL showed a conversion from a purely CD8+ response to a high proportion of CD4+ clones following vaccination. A prominent acute-phase response manifested by a five- to tenfold increase in C-reactive protein was observed, as was a systemic eosinophila. Vaccination resulted in the regression of axillary lymphatic metastases, stabilisation of pulmonary metastases, and a dramatic, reversible increase in cerebral oedema associated with multiple central nervous system metastases: however, lesions in the adrenal glands, pancreas and spleen proved refractory. The antitumour effects and immune response were not detectable 2 months following the last vaccination. Irradiation of the extensive cerebral metastases resulted in rapid deterioration and death of the patient.

Autopsy↗
PubMed1997

Mapping of conformational B cell epitopes within alpha-helical coiled coil proteins.

An approach to mapping antigenic B cell epitopes within alpha-helical coiled coil proteins has been developed and applied to two proteins: Streptococcal M protein and C. elegans paramyosin protein UNC-15. Overlapping peptides derived from an alpha-helical coiled coil conformational epitope were embedded between helical flanking peptides derived from the completely unrelated GCN4 leucine zipper peptide. The resulting chimeric peptides exhibited helical propensity. Chimeric peptides were tested for antigenicity (recognition by antibody) or immunogenicity (production of appropriate antibody response). A conformational epitope within the Streptococcal M protein recognised by three mAbs spanned 12 residues. Analysis of chimeric peptides based on C. elegans UNC-15 has enabled fine mapping of the minimal B cell epitope recognised by monoclonal antibody NE1-6B2 to seven non-contiguous residues (spanning 15 residues); the footprint of contact residues involved in antibody recognition being restricted to the hydrophilic face of the helix and covering five helical turns. This chimeric peptide epitope when coupled to diphtheria toxoid was highly immunogenic in mice and antisera recognised the conformationally dependent native peptide epitope. This approach has the potential to map conformational epitopes and design minimal epitopes for use as vaccine candidates.

Amino Acid Sequence↗