Biomedical subjects

M F Good

Publications and source records attributed to M F Good.

At least 91 records · Page 5Linked to original sources

PubMed1992

Promiscuous malaria peptide epitope stimulates CD45Ra T cells from peripheral blood of nonexposed donors.

PBL from individuals with no history of malaria exposure, as well as cord blood lymphocytes, were tested for proliferation to T cell epitopes from the malaria circumsporozoite proteins of Plasmodium falciparum and Plasmodium vivax. Cells from many individuals proliferated in response to these peptides, but for two peptides (P. vivax317-336 and P. falciparum CS331-350) the response rate ranged from 64 to 93%, with the specific stimulation indices reaching as high as 38. The phenotype of the cells responding to PfCS331-350 was predominantly CD4+,CD8-,CD45Ra+,CD45Ro-, which was the inverse of the phenotype of the cells responding to tetanus toxoid with respect to CD45 isoforms. T cell clones from different individuals specific for PfCS331-350 were restricted by at least four different HLA-DR molecules and there was no evidence that the peptide was a "superantigen." Overlapping peptides were used to demonstrate that clones had different fine specificities although the peptide specificities of the DR4-restricted and DR11-restricted clones were similar. Although the individuals tested here have had no history of malaria exposure, these data demonstrate that they have T cells specific for malaria sequences present in high frequency that proliferate as intensely as some memory responses. Although one clone from an individual with a history of BCG vaccination did react strongly with PPD, the phenotype of these cells suggests that they are not classical memory cells for a cross-reactive recall Ag. Such cells may affect the induction or expression of malaria immunity.

Amino Acid Sequence↗

PubMed1992

High frequency of malaria-specific T cells in non-exposed humans.

A major goal of current candidate malaria vaccines is to stimulate the expansion of clones of malaria-specific lymphocytes. We have examined the in vitro T cell responses of a group of malaria exposed and non-exposed adult Caucasian donors to recombinant circumsporozoite (CS) proteins, one of which is undergoing clinical trials, to blood-stage parasites, and to synthetic peptides copying the CS protein and defined blood-stage proteins. In nearly all individuals tested, CD4 T cell proliferation or lymphokine production occurred in response to whole parasite or CS protein stimulation, and T cells from many individuals responded to synthetic peptides. T cell responses were major histocompatibility complex-restricted, and stimulation of T cells with malaria parasites or CS protein did not appear to expand a population of T cell receptor gamma/delta cells. Malaria-specific responses were independent of prior malaria exposure, and in some cases exceeded the magnitude of response to tetanus toxoid. Specific T cells are present in high frequency in the peripheral blood of many donors who have never been exposed to malaria. Although malaria-specific CD4 T cells play an important role in immunity, these data question whether vaccines need to stimulate such cells, and focus attention on other aspects of malaria immunity which may be more critical to a successful vaccine.

Amino Acid Sequence↗

PubMed1992

A malaria vaccine strategy based on the induction of cellular immunity.

In this article, Michael Good offers an alternative to the current emphasis on developing subunit, humoral-response-inducing malaria vaccines. He develops a three-pronged proposal comprising (1) a greater emphasis on cellular immunity, (2) analysis of the role of the spleen in protection, and (3) the development of an attenuated vaccine.

Animals↗

PubMed1992

Malaria vaccines.

Explore the source record for details and available documents.

Amino Acid Sequence↗

PubMed1992

The importance of T cell homing and the spleen in reaching a balance between malaria immunity and immunopathology: the moulding of immunity by early exposure to cross-reactive organisms.

It takes a number of years to develop clinical immunity to malaria and malaria pathology is also most evident a number of years after birth. T cells are known to play an important role in defence from malaria parasites but may also contribute to the disease symptoms associated with malaria. T cells which react against malaria parasites have arisen through stimulation with organisms which cross-react with malaria or through exposure to the malaria parasites themselves and express a memory phenotype (CD45Ro+, CD45Ra-, CD4+). T clones which have arisen through exposure to cross-reactive organisms may be expected to home to the tissues where initial exposure occurred as determined by tissue-specific adhesion molecules on the lymphocyte surface. Such tissues may not be appropriate to parasite killing and localization of T cells in such sites may contribute to the immunopathology of malaria. The sharp increase in immunity and decline in pathology observed in later childhood in malaria endemic areas may result from an increase in the number of T cells induced by the parasite itself (as opposed to cross-reactive organisms). Such T cells may not have a preferential trafficking to other organs and may be more likely to circulate through the spleen. Splenic changes may also allow more malaria-specific T cells to concentrate in the spleen and may facilitate interactions between T cells, monocytes, neutrophils and parasites resulting in parasite death. Whereas cytokines secreted by parasite-reactive T cells in all locations may contribute to cerebral malaria and other forms of pathology, cytokines in the spleen at least, should directly contribute to parasite death.

Age Factors↗

PubMed1992

'Natural' T cells responsive to malaria: evidence implicating immunological cross-reactivity in the maintenance of TCR alpha beta+ malaria-specific responses from non-exposed donors.

It is now generally accepted that peripheral blood of humans not exposed previously to malaria contains T cells which proliferate vigorously in response to malaria parasites and antigens. Although it has been claimed that these cells express a memory phenotype, their origin is uncertain. We have examined the phenotype and immunological responses of such cells. We confirm that these cells do express the 'memory phenotype', CD45Ro, in that depletion of such cells, but not of CD45Ra (virgin) cells, abrogates the immune response to malaria parasites. In an effort to define the genesis of these responses, numerous malaria-specific T cell clones have been generated from non-exposed individuals. These were tested for reactivity to a large panel of common bacterial, viral, and fungal pathogenic and non-pathogenic organisms. Most clones proliferated vigorously in response to one or more such organisms, while many clones demonstrated smaller but significant degrees of proliferation in response to many different organisms. Our data offers insights into the maintenance of immunological memory. All clones examined were CD3+, CD4+, CD8-, TCR alpha beta+, and TCR delta-. The ratio of TCR alpha beta+ to TCR delta+ cells among peripheral blood lymphocytes increased during polyclonal culture in the presence of parasite. The high frequency of such cells in peripheral blood (1/800-1/9000), and their response to a wide range of geographically different Plasmodium falciparum isolates and clones by both proliferation and lymphokine secretion (predominantly IFN-gamma) with a high degree of sensitivity (less than 1 parasite/microliters blood in some cases) suggests that these cells must be quickly activated following malaria infection. Their contribution to the outcome of the disease (protection/immunopathology) may be significant.

Animals↗

PubMed1992

Development of a malaria T-cell vaccine for blood stage immunity.

We have defined a strategy for the development of a T-cell vaccine for blood stage immunity, taking into consideration the central role of T cells and MHC restriction in malaria immune responses. We have used the AMPHI computer algorithm to identify putative T-cell epitopes from conserved regions of 11 Plasmodium falciparum asexual stage proteins. Ten of the eleven proteins are currently candidates for vaccine development. Using this algorithm we selected 22 putative T-cell epitope peptides and 8 control peptides. These peptides were used to test the T-cell responses of three defined populations of Caucasians who have (1) recovered from P. falciparum malaria, (2) been exposed, but never clinically infected, (3) never been exposed or infected. Preliminary analysis of our data shows population differences in T-cell responses to putative T-cell epitope peptides. Ultimately, these studies will help to identify those T epitopes that can be incorporated into a T-cell vaccine for protective immunity.

Animals↗

PubMed1992

Geographically restricted heterogeneity of the Plasmodium falciparum circumsporozoite protein: relevance for vaccine development.

The design of a subunit vaccine against the malaria parasite relies on the epitopes recognized by T cells being identified and polymorphisms therein being defined. Here we present the analysis of a 354-bp fragment of the circumsporozoite (CS) protein encompassing defined proliferative and cytotoxic T-cell recognition regions. We reveal that the polymorphism of CS protein T-cell sites appears to be very limited among Plasmodium falciparum isolates prevalent in certain geographical regions, in particular Papua New Guinea. Furthermore, the more extensive polymorphism noted in other areas appears to be restricted. Although the extent of variation observed for the T-cell recognition domains suggests that any vaccine designed to stimulate this form of immunity will need to be polyvalent, this variation appears to be finite and the combination of peptides necessary for inclusion in a polyvalent vaccine may be small. If ways to increase immune responsiveness can be found, then a vaccine designed to stimulate CS protein-specific T-cell activity may prevent malaria.

Amino Acid Sequence↗

PubMed1992

Plasmodium falciparum CS protein--prime malaria vaccine candidate: definition of the human CTL domain and analysis of its variation.

Studies in mice have shown that immunity to malaria sporozoites is mediated primarily by cytotoxic T lymphocytes (CTL) specific for epitopes within the circumsporozoite (CS) protein. Humans, however, had never been shown to generate CTL against any malaria or other parasite protein. The design of a sub-unit vaccine for humans relies on the epitopes recognized by CTL being identified and polymorphisms therein being defined. We have developed a novel technique using an entire series of overlapping synthetic peptides to define the epitopes of the Plasmodium falciparum CS protein recognized by human CTL and have analyzed the sequence variation of the protein with respect to the identified CTL epitopic domain. We have demonstrated that some humans can indeed generate CTL against the P. falciparum CS protein. Furthermore, the extent of variation observed for the CTL recognition domain is finite and the combination of peptides necessary for inclusion in a polyvalent vaccine may be small. If ways can be found to increase immune responsiveness, then a vaccine designed to stimulate CS protein-specific CTL activity may prevent malaria.

Animals↗

PubMed1991

Role of intrastructural/intermolecular help in immunization with peptide-phospholipid complexes.

The design of effective subunit vaccines requires the inclusion of both B and T cell epitopes. The best mechanism for including both types of epitopes within an Ag is dependent upon how the Ag is processed by the APC for presentation to a responsive Th cell. If it is more efficient to process a single molecule for both helper and primary epitopes, than covalent linkage of B cells and T cell epitopes for intramolecular presentation of help would be recommended. If however, separate peptides containing either B or Th cell epitopes could be included within a single complex for the elicitation of intermolecular/intrastructural help, more antigenically diverse structures could be designed. This paper reports that it is possible to generate intermolecular/intrastructural help within an antigenic peptide-phospholipid (PL) complex. These peptide-PL complexes use well defined epitopes from Plasmodium falciparum as Ag. In addition to generating intrastructural help, we have shown that the Ir to these peptide-PL complexes is controlled by Ir genes and is similar to the Ir to the circumsporozoite protein of this pathogen.

Animals↗

PubMed1991

Towards the development of the ideal malaria vaccine. A decade of progress in a difficult field.

Malaria remains one of the world's most serious diseases, affecting the lives of up to 500 million people. The rapid development of drug resistance enhances the need for the development of a vaccine. Since the first cloning of malaria proteins early in the last decade, there have been a number of "subunit" vaccine trials involving humans and monkeys. During this time, our understanding of the basic immunobiology of malaria has increased; different immune mechanisms are required to combat the different stages in the life cycle of the parasite, and the future vaccine will have to stimulate these different effector mechanisms. There has been steady progress over the last decade toward an effective vaccine, but a great deal of further effort is still required.

Amino Acid Sequence↗

PubMed1991

Molecular analysis of T and B cell repertoires in mice immunized with Opisthorchis viverrini antigens.

B10 mice were immunized with an Opisthorchis viverrini somatic extract and then their responses were analyzed. The antigenic fractions of the extract were separated by SDS-polyacrylamide gel electrophoresis, electroblotted to nitrocellulose membranes and solubilized for use in lymphocyte culture. Antibody specificity was also visualized by immunoblotting using immunized mouse sera. The Mr of the main immunogenic fractions for T cells ranged from 28 to 46 kDa, whereas those recognized by antibodies were 45, 52, 56, 59, 65, 69, 75 and 81 kDa. The results indicate a striking difference in the antigenic recognition pattern of T and B cells which may be important for selecting antigen molecules for immunological studies of this trematode infection in man.

Animals↗

PubMed1991

The implications for malaria vaccine programs if memory T cells from non-exposed humans can respond to malaria antigens.

Although the goal of current candidate vaccines is to expand a population of malaria antigen-specific lymphocytes, accumulating evidence suggests that peripheral blood of adult humans contains significant numbers of malaria-specific T cells prior to any exposure to vaccine or actual infection. The reason why such naive humans are susceptible to malaria infection may thus relate not to inadequate T-cell surveillance but to some other factor--possibly lack of suitable splenic modification. It is possible that current vaccine programs are misdirected because these other factors are not being addressed. The possibility of an attenuated vaccine should be re-examined.

Animals↗

PubMed1991

Location of human cytotoxic T cell epitopes within a polymorphic domain of the Plasmodium falciparum circumsporozoite protein.

Studies in mice have shown that cytotoxic T lymphocytes (CTL) specific for epitopes within the circumsporozoite (CS) protein of malaria sporozoites can prevent malaria probably by destroying infected hepatocytes. This has provided a model for the development of a sporozoite vaccine. It has not been shown whether humans can mount a CTL response to this protein nor what determinants on the protein could be considered as target epitopes for such cells and thus merit inclusion in a sporozoite vaccine. We have used a novel technique to study a caucasian population which would benefit from a sporozoite vaccine and have been able to demonstrate that some individuals with a history of sporozoite exposure do contain peripheral blood CTL specific for the Plasmodium falciparum CS protein. The prevalence of CTL among different individuals is low and there is evidence that recent malaria exposure may be a prerequisite for finding such CTL. In three individuals, CTL could be repeatedly found and in all cases the epitopes mapped to one of the two polymorphic C-terminal domains. Using a CTL line, we mapped a recognition site to residues 351-395 of the CS protein, overlapping the region of the protein recognized by murine CTL.

Adult↗

PubMed1991

Inability of Plasmodium vinckei-immune spleen cells to transfer protection to recipient mice exposed to vaccine 'vectors' or heterologous species of plasmodium.

Mice can be immunized to Plasmodium vinckei by repeated infections followed by cure. Such immunity is dependent on CD4 T cells and an architecturally modified spleen, but has little requirement for antibody. Thus, athymic mice can be exposed to P. vinckei and cured, but do not develop immunity. They are resistant to challenge with parasites, however, if they are then given spleen cells from euthymic immunized animals. Such immune spleen cells, however, cannot transfer resistance to normal mice which have been exposed to BCG, Salmonella typhimurium, or vaccinia virus, and are only partially effective in transferring resistance to mice which have been previously immunized with heterologous plasmodia, P. yoelii, P. chabaudi and P. berghei. Mice exposed to varying numbers of irradiated P. vinckei-pRBC do not develop immunity and nor are such animals protected following adoptive transfer of immune spleen cells. Cellular immunity to malaria may not only be dependent on a population of immune CD4 T cells, but may require a specifically architecturally modified spleen which may not occur following either exposure to candidate vaccine vectors, heterologous plasmodia or non-viable homologous plasmodia.

Animals↗

PubMed1991

Effect of initial treatment of chronic inflammatory periodontal disease on the frequency of peripheral blood T-lymphocytes specific to periodontopathic bacteria.

Limit dilution analysis (LDA) was used to determine the effect of initial treatment of chronic inflammatory periodontal disease on the frequency of periodontopathic bacteria-specific T-cells in peripheral blood. Eleven marginal gingivitis (MG) and 8 adult periodontitis (AP) subjects took part in the study. The proliferative T-lymphocyte precursor (PTL-P) frequencies to Porphyromonas gingivalis and Actinomyces viscosus were determined using LDA and Poisson statistics both before and after treatment. Tetanus toxoid was used as a control antigen. Treatment resulted in a significant reduction in clinical disease parameters in both groups. The median peak PTL-P frequency for P. gingivalis was significantly higher in the AP group compared with the MG group before treatment. This was not the case after treatment nor with A. viscosus. In the MG group the median peak PTL-P frequency with both P. gingivalis and A. viscosus declined as a result of treatment. Although this decline was not statistically significant it may indicate an antigen-specific response in this group. In the AP group the median peak PTL-P frequency with P. gingivalis before treatment was 83.76 x 10(-6) (approximately 1 in 12,000) and after treatment it was 36.17 x 10(-6) (approximately 1 in 28,000). Dose-response relationships showed at each concentration of organisms/well this trend for a decline in PTL-P frequency after treatment, suggesting that any increased responsiveness to this organism in this group may be largely antigen-specific. However, there was no difference in this group in the median peak PTL-P frequency with A. viscosus before and after treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Actinomyces viscosus↗

PubMed1990

Cytotoxic T cells recognize a peptide from the circumsporozoite protein on malaria-infected hepatocytes.

Irradiated malaria sporozoites can induce CD8+ T cells that are required for protection against infection. However, the parasite antigens targeted by this immune response are unknown. We have discovered a 16-amino acid epitope from the Plasmodium yoelii circumsporozoite (CS) protein that is recognized by cytotoxic T cells from immune mice. Lymphocytes stimulated with this peptide can kill P. yoelii liver stage parasites in vitro in an MHC-restricted, antigen-specific manner. Thus, epitopes from the CS protein are presented on the surface of infected hepatocytes and can be targets for T cells, even though intact CS protein has not been detected on the surface of the infected hepatocyte. A vaccine that induced CTL to parasite antigens might protect humans against malaria by eliminating liver stage parasites.

Animals↗

PubMed1990

Adoptive transfer of CD8+ T cells from immune animals does not transfer immunity to blood stage Plasmodium yoelii malaria.

The malaria parasite, Plasmodium yoelii 17X, causes a self-limited, nonlethal infection characterized, in the blood stage, by preferential invasion of reticulocytes. Previous studies have suggested that immunity to the blood stage infection may be related to enhanced levels of class I MHC Ag on the parasitized reticulocyte surface and can be adoptively transferred to immunodeficient mice by immune CD8+ T cells in the absence of CD4+ T cells. To further examine the mechanisms of CD8+ T cell involvement in immunity to blood stage P. yoelii infection, we performed in vivo CD8 depletion and adoptive transfer experiments. Depletion of CD8+ T cells during primary blood stage infection in BALB/c mice did not diminish the ability of the mice to resolve their infections. Spleen cells from immune BALB/c and C57BL/10 mice were transferred to BALB/c-nu/nu and C57BL/10-nu/nu mice, respectively. The recipient mice were CD4 depleted in vivo to kill any transferred CD4+ T cells. The mice failed to control the infection. Populations of CD4-, CD8+ T cells were transferred from immune CBA/CaJ donors to in vivo CD4-depleted CBA/CaJ recipients. The mice were unable to control the infection. Although immune unfractionated spleen cells transferred rapid protection in all three mouse strains and immune CD4+ T cells transferred immunity in the two mouse strains studied, CD8+ T cells by themselves were neither protective nor did they enhance immunity.

Animals↗