Search PubMed⌕ Search

Biomedical subjects

M F Good

Publications and source records attributed to M F Good.

At least 109 records · Page 6Linked to original sources
PubMed1990

Peptide analysis of the T cell response to the malaria circumsporozoite (CS) protein.

The T cell response to the circumsporozoite (CS) protein is still not well understood. There is still not agreement on the degree of immunological non-responsiveness or even on the basic question of whether the response to native CS protein requires T cells at all. Recombinant proteins and synthetic peptides are tools that are helping us learn the basics of the immune response to this protein. Here, the human and murine responses to the protein are probed using these valuable research tools. Then, the possibility of using peptide vaccines is discussed.

Amino Acid Sequence↗
PubMed1990

Clonal analysis of the effect of iron on human cytotoxic and proliferating T lymphocytes.

The immunoregulatory effect of non-transferrin-bound iron (Fe3+) on the proliferative and cytotoxic responses of normal human T lymphocytes was studied using a sensitive limit-dilution technique capable of detecting the responses of individual lymphocytes. Iron, present in the form of ferric citrate at concentrations from 0.03 to 1.0 mmol/L, significantly reduced the cloning frequency of peripheral blood T lymphocytes. The effect of iron appeared, however, to be targeted to individual clones in that some clones that did grow in the presence of iron achieved a normal rate of proliferation. Thus, iron was not non-specifically toxic. At these same concentrations ferric citrate also produced significant reductions in the cloning frequency of CD4+ CD8-precursor T lymphocytes. Reductions in the response of T lymphocyte precursors capable of cytotoxic activity occurred in the presence of ferric citrate from 0.1 to 1.0 mmol/L. These data support the hypothesis that non-transferrin-bound iron has an immunoregulatory role in cell-mediated immunity.

Antibodies, Monoclonal↗
PubMed1990

Major population differences in T cell response to a malaria sporozoite vaccine candidate.

Using a complete series of overlapping peptides, we have identified the T cell epitopes of a malaria vaccine candidate, the circumsporozoite (CS) protein, that are recognized by sporozoite-exposed residents of a non-endemic country. This protein and subunits from it are being considered as malaria sporozoite vaccine candidates, as CS-specific antibodies and cytotoxic T lymphocytes have been shown to have a role in protection. The rationale for developing an antibody-based vaccine is that in Plasmodium falciparum the immunodominant B cell epitope of the protein, (Asn-Ala-Asn-Pro)n [(NANP)n], is invariant. However, the ideal vaccine must contain CS protein-derived T cell antigenic epitopes to allow natural boosting of the antibody response following sporozoite exposure. Here, we show that major differences occur between the CS-specific T cell responses of non-endemic Caucasians and an endemic African population. HLA differences between the populations are, in part, responsible. Subunit malaria vaccines for one population may be ineffective in a different population.

Animals↗
PubMed1990

Evidence implicating MHC genes in the immunological nonresponsiveness to the Plasmodium falciparum CS protein.

The circumsporozoite (CS) protein is a major candidate vaccine antigen for the sporozoite stage of malaria. Both cytotoxic T cells (CTL) and antibody specific for the CS protein are thought to be important in protection. By examining the immune response in mice and humans we have shown that genes mapping to the major histocompatibility complex (MHC) are important for immune responsiveness. F1 mice between high antibody responders and low antibody responders are high antibody responders, suggesting that in this model immune suppressor genes do not control the immune response. Using synthetic peptides to map epitopes for CTL and helper T cells (which are important for the antibody response) we have shown that the T-cell epitopes are located in the polymorphic region of the protein, and we hypothesize that T cells have indeed selected the variation observed in the CS protein. The success of subunit vaccines will depend on the pattern of variation in different geographical locations, the ability to construct multivalent vaccines containing different variant epitopes from this protein, and on the existence of other sporozoite and liver-stage proteins involved in protection.

Animals↗
PubMed1990

A CTL epitope on the circumsporozoite protein of P. yoelii.

Humans are infected with malaria by the bite of anophelene mosquitos carrying plasmodia sporozoites. These sporozoites pass quickly from the blood into hepatocytes, where they develop into mature liver-stage parasites over several days. The clinical stage of the illness begins only when the liver-stage parasites rupture into the bloodstream and erythrocytes are invaded. The pre-erythrocytic stages of malaria are inviting targets for vaccine development, because an effective immune response to these early stages would prevent symptomatic infections.

Amino Acid Sequence↗
PubMed1990

Genetic restriction of protective immunity to Plasmodium yoelii sporozoites.

Ten congenic strains of mice were immunized with irradiated sporozoites of Plasmodium yoelii. When challenged with viable sporozoites, only two strains had a high proportion of animals which did not develop blood-stage infections. Genes both within and outside the H-2 region affected the degree of protection. Immunity did not correlate with anti-sporozoite antibody levels. In vivo depletion of CD8+ T cells did not alter immunity in two of three congenic strains, implying the existence of a novel mechanism of cell-mediated immunity.

Animals↗
PubMed1990

Malaria vaccine development: recent progress towards a sporozoite vaccine.

Malaria affects the lives of hundreds of millions of people. Drug therapy is becoming less effective, a vaccine has yet to be developed, and one to two million children die annually as a result of malaria. In the last 10 years, however, there has been great progress towards a vaccine. A number of important antigens have been cloned, including the circumsporozoite (CS) protein which covers the sporozoite and which is a target for antibody and cytotoxic T lymphocytes. In laboratory models, successful vaccination has been achieved with some CS constructs. Although successful immunization with irradiated sporozoites has been achieved in the laboratory, the lack of immunity following natural exposure to sporozoites in endemic countries is puzzling. Parasite variation, host genetic factors and immunological tolerance may each contribute to this situation. Identification of other important antigens and a better understanding of host immune responses to sporozoite and liver stage antigens should be important steps towards rational vaccine design.

Antigens, Protozoan↗
PubMed1989

Genetic control of immunity to Plasmodium yoelii sporozoites.

Using a rodent malaria system, we have shown that protective immunity to the preerythrocytic stages of malaria is genetically controlled by MHC and non-MHC genes. Ten congenic strains of mice were immunized with irradiated sporozoites of Plasmodium yoelii. When challenged with viable sporozoites, only two strains had a high proportion of animals that did not develop blood stage infections. Immunity did not correlate with antisporozoite antibody levels. Two protective mechanisms exist determined by non-H-2 genes, and each mechanism is further controlled by H-2-linked Ir genes. On the BALB background only H-2d mice are protected, and protection is abolished by depleting CD8+ T cells. In contrast, on the B10 background only H-2q mice are strongly protected, and protection is not affected by CD8+ T cell depletion. If similar complex genetic regulation of immunity occurs in the human malarias, it will be a major hurdle for vaccine development.

Animals↗
PubMed1989

Interdependence of CD4+ T cells and malarial spleen in immunity to Plasmodium vinckei vinckei. Relevance to vaccine development.

We studied immunity to the blood stage of the rodent malaria, Plasmodium vinckei vinckei, which is uniformly lethal to mice. BALB/c mice develop solid immunity after two infections and drug cure. The following experiments define the basis of this immunity. Transfer of pooled serum from such immune mice renders very limited protection to BALB/c mice and no protection to athymic nu/nu mice. Moreover, B cell-deficient C3H/HeN mice develop immunity to P. vinckei reinfection in the same manner as immunologically intact mice, an observation made earlier. In vivo depletion of CD4+ T cells in immune mice abrogates their immunity. This loss of immunity could be reversed through reconstitution of in vivo CD4-depleted mice with fractionated B-, CD8-, CD4+ immune spleen cells; however, adoptive transfer of fractionated CD4+ T cells from immune spleen into naive BALB/c or histocompatible BALB/c nude mice does not render recipients immune. In vivo depletion of CD8+ T cells did not influence the parasitemia in nonimmune or immune mice. Splenectomy of immune mice completely reverses their immunity. Repletion of splenectomized mice with their own spleen cells does not reconstitute their immunity. We conclude that some feature of the malaria-modified spleen acts in concert with the effector/inducer function of CD4+ T cells to provide protection from P. vinckei. To be consistent with this finding, a malaria vaccine may require a combination of malaria Ag to induce immune CD4+ T cells and an adjuvant or other vaccine vehicle to alter the spleen.

Animals↗
PubMed1989

Human T cell recognition of polymorphic epitopes from malaria circumsporozoite protein.

Lymphocytes obtained from forty individuals living in a malaria endemic area of West Africa were tested for in vitro proliferative responses to peptides representing variant regions of the immunodominant T cell domain of the circumsporozoite protein (amino acids 326 to 345, referred to as Th2R, and 361 to 380, referred to as Th3R) from three distinct strains of Plasmodium falciparum. A total of 83% of the individuals responded to at least one of the six peptides tested, confirming that these epitopes are immunodominant. A much greater number of individuals than expected by chance (32% of the responders to Th2R and 27% of the responders to Th3R) reacted to all three of the variant peptides for that epitope, indicating interdependency of the T cell responses, suggestive of cross-reactivity. Nevertheless, some subjects' T cells were clearly able to distinguish each variant peptide from the others. Using EBV transformed B cells, lymphocytes from 10 of the individuals were HLA typed. In this small group, HLA DRw13 was associated with a positive response to any of the peptides, whereas there was a negative association between DQw3 and response to any of the peptides. These results, although limited by the small sample size, suggest that recognition of T epitopes may be Ir gene linked. Our findings suggest that it may be possible to broaden the immunogenicity of an anti-sporozoite malaria vaccine.

Adult↗
PubMed1989

The immunologic significance of variation within malaria circumsporozoite protein sequences.

We have previously suggested that variation within the circumsporozoite protein of the malaria parasite Plasmodium falciparum was the result of selection by immune T cells. Our hypothesis has been supported by experiments documenting a lack of cross-reactivity between variant peptides from the C-terminal region for murine T cells primed by 7G8-specific sequences. Now, by using a murine model we have found that peptides representing variant regions (amino acid residues 326-343 and 361-380) of two other parasite clones (Wel and LE5) are also immunodominant for murine T cells. However, there were distinct changes in response profiles. For example, whereas lymph node cells from H-2d and H mice immunized with peptides from the 326-343 region of all three variants proliferated in vitro after homologous challenge, only lymph node cells from H-2b mice immunized with LE5 peptide proliferate after homologous challenge. In contrast, only LE5 did not induce lymphoproliferation against homologous challenge in the H-2s background. These data suggest that the naturally occurring substitutions affect agretopic (i.e., Ia). Peptides from all variants representing the 361-380 domain were recognized only by T cells from H-2k mice. Also, in nearly all cases, T cells primed by one sequence did not recognize variant sequences. The immunodominance of these domains from three different clones and the lack of significant cross-reactivity further supports the hypothesis that variation is the result of T cell immune pressure.

Amino Acid Sequence↗
PubMed1989

Restricted or absent immune responses in human populations to Plasmodium falciparum gamete antigens that are targets of malaria transmission-blocking antibodies.

We have studied the antibodies to sexual stage antigens of Plasmodium falciparum in human sera from Papua New Guinea where intense transmission of P. falciparum occurs as well as the less prevalent P. malariae and P. vivax. In extracts of gametes of P. falciparum we have studied the reactivity of serum antibodies with antigens labeled with 125I on the surface of the gametes as well as intracellular gamete antigens. A prominent 27-kD sexual stage-specific intracellular protein was recognized more or less in proportion to the general antibody response to gamete proteins. The response to the gamete surface proteins, however, was quite unrepresentative of the general antibody response to the intracellular gamete proteins. No antibodies were detected against Pfs25, a 21-kD protein expressed on zygotes and ookinetes of P. falciparum and known to be a sensitive target of malaria transmission-blocking antibodies. The antibody response to two other target antigens of transmission-blocking antibodies on the surface of gametes of P. falciparum, a 230- and a 48- and 45-kD protein doublet, was very variable and independent of the response to the internal protein antigens. Several possibilities are discussed that may account for the variable response to these gamete surface antigens in individuals with otherwise good antibody responses to internal sexual stage proteins. Among these is the possibility that there is MHC restriction of the immune response to the gamete surface antigens in the human population. This interpretation accords well with evidence for MHC-restricted immune response to the same P. falciparum gamete surface antigens in studies with H-2 congenic mice (24).

Animals↗
PubMed1989

Involvement of T cells in malaria immunity: implications for vaccine development.

T cells are critical for immunity to malaria, not only because they function as helper cells for an antibody response, but also because they serve as effector cells. Such cellular immunity is directly implicated in protection from sporozoites and plays an important role in protection from blood-stage parasites. It also can block transmission of malaria from mammalian host to the mosquito. Both CD8 and CD4 effector cells have important roles. The parasite's defence from immune attack, however, is designed to minimize activation of T cells. Thus, there appears to be limitation of the number of T sites within many malaria proteins and variation within these limited sites. Homology to host proteins and resultant immune-escape due to tolerance may be another mechanism. These parasite defence mechanisms highlight both the importance of T-cell immunity in malaria and the challenge of designing effective vaccines to stimulate T cells.

Animals↗
PubMed1989

IL-2 and IL-4 can co-modulate the generation of cytotoxic T cells through CD8- CD4- splenic lymphocytes.

Following activation with concanavalin A (Con A), murine T cells are able to suppress the generation of allospecific cytotoxic T lymphocytes (CTL). We have analysed the phenotype, tissue distribution, and mode of action of these cells in an effort to understand further the regulation of CTL-mediated immunity. The precursors of such cells are rare (1 cell per 70,000 spleen cells being able to suppress the generation of a particular allospecific response), but are much more abundant in the spleen than in the thymus. By the use of cytotoxic antibodies, we have been able to demonstrate that the splenic precursors of such cells are Thy-1.2+, CD4-, CD8- but, following activation with Con A, these cells acquire the CD8 marker. Cellular suppression by these lymphocytes is dramatically increased in the presence of the Th2-derived lymphokine, IL-4, whereas IL-2, the Th1-derived lymphokine, significantly augments the generation of CTL in a mixed lymphocyte culture even though relative suppression is still evident in the presence of Con A-activated lymphocytes. Suppression is not due to overcrowding of a cell culture since adding Con A-activated cells to an A anti-B + C culture often resulted in the suppression of the A anti-B response but not the A anti-C response, or vice versa. Suppression appears to require cellular interaction since supernatants from Con A-activated lymphocytes are unable to mediate suppression. Such cells may play an important intermediate role in homeostasis.

Adjuvants, Immunologic↗