Protection against Plasmodium falciparum malaria in chimpanzees by immunization with the conserved pre-erythrocytic liver-stage antigen 3.

In humans, sterile immunity against malaria can be consistently induced through exposure to the bites of thousands of irradiated infected mosquitoes. The same level of protection has yet to be achieved using subunit vaccines. Recent studies have indicated an essential function for intrahepatic parasites, the stage after the mosquito bite, and thus for antigens expressed during this stage.

A novel Plasmodium falciparum sporozoite and liver stage antigen (SALSA) defines major B, T helper, and CTL epitopes.

In the search for subunit vaccines that are able to induce the type of sterile, protective immunity achieved by irradiated sporozoites, there is increasing evidence that defense mechanisms directed at the intrahepatic stage and Ags expressed at this stage are critical. We have initiated a systematic search for such molecules and report here the identification and partial characterization of a novel Plasmodium falciparum gene encoding a 70-kDa protein, expressed in both sporozoite and liver stages (SALSA), with a vaccine potential that stems from its antigenic features. Antigenicity and immunogenicity studies were conducted in individuals exposed to malaria, in immunized mice, and in chimpanzees, using a recombinant protein and two synthetic peptides.

Identification of an Mhc-DPB1 allele involved in susceptibility to experimental autoimmune encephalomyelitis in rhesus macaques.

Experimental autoimmune encephalomyelitis (EAE) is an inducible autoimmune disorder that in rodents is known to be influenced by genetic background, specifically the Mhc class II region. Immunization of a group of outbred rhesus macaques with bovine high homogenate results in induction of the disease in approximately 65% of the animals. No clear association between the Mamu-DR or -DQ subregion of the rhesus macaque MHC (MhcMamu) and susceptibility or resistance to the disease has been documented.

Allelic diversity at the Mhc-DP locus in rhesus macaques (Macaca mulatta).

Allelic diversity at the major histocompatibility complex class II DP locus of rhesus macaques was studied by sequencing exon 2 of Mamu-DPA1 and -DPB1 genes. The Mamu-DPA1 gene is apparently invariant, whereas the Mamu-DPB1 locus displays polymorphism. Here we report the characterization of 1 Mamu-DPA1 and 13 Mamu-DPB1 alleles which were compared with other available primate Mhc-DPA1 and -DPB1 sequences.

Gel electrophoretic analysis of rhesus macaque major histocompatibility complex class II DR molecules.

Rhesus macaque MHC class II DR molecules were isolated from radiolabeled B-cell line extracts by immunoprecipitation with the mAbs 7.3.19.

Expansion and contraction of rhesus macaque DRB regions by duplication and deletion.

Previous sequence analysis of the rhesus macaque MHC (MhcMamu) class II DRB region has allowed the detection of at least 34 alleles belonging to different lineages. In this communication, 36 new Mamu-DRB alleles are reported. The gene content of the DRB region has been determined for several homozygous animals of consanguineous origin.

Chimpanzees and supporting models in the study of malaria pre-erythrocytic stages.

Chimpanzees are being used in the study of immune response to Plasmodium falciparum malaria pre-erythrocytic stages (MPES). Responses induced by immunisation with recombinant/synthetic antigens and by irradiated sporozoites are being evaluated in a model system that is phylogenetically close to humans and that is amenable to limited manipulation not possible in humans. The value of chimpanzees for the in-depth study of immunological mechanisms at work in MPES-induced protection are discussed.

The biologic importance of conserved major histocompatibility complex class II motifs in primates.

Phylogenetic comparisons of polymorphic second-exon sequences of MHC class II DRB genes showed that equivalents of the HLA-DRB1*03 alleles are present in various nonhuman primate species such as chimpanzees, gorillas, and rhesus macaques. These alleles must root from ancestral structure(s) that were once present in a progenitor species that lived about 35 million years ago. Due to accumulation of genetic variation, however, sequences that cluster into a lineage are generally unique to a species.

Evolutionary conservation of major histocompatibility complex-DR/peptide/T cell interactions in primates.

Many major histocompatibility complex (MHC) polymorphisms originate from ancient structures that predate speciation. As a consequence, members of the Mhc-DRB1*03 allelic lineage are not only present in humans but in chimpanzees and rhesus macaques as well. This emphasizes that Mhc-DRB1*03 members must have been present in a common ancestor of these primate species that lived about 30 million years ago.

Major histocompatibility complex class II DQ diversity in rhesus macaques.

By the use of restriction fragment length polymorphism analysis 10 Taq I fragments could be identified for the MhcMamu-DQA1 region. A strong correlation exists between the occurrence of Mamu-DQA1/Taq I fragments and Mamu-DQA1 allelic sequence variation. Most restriction fragments correspond with a unique Mamu-DQA1 allele, with one exception being the Taq I 4.

Evolutionary stability of transspecies major histocompatibility complex class II DRB lineages in humans and rhesus monkeys.

Sequence analysis of rhesus monkey (Macaca mulatta) polymorphic second exon of major histocompatibility complex class II DRB subregion genes demonstrates the existence of at least 34 alleles. Some of these rhesus monkey alleles are very similar (or nearly identical) to HLA-DRB alleles. These data demonstrate that members of the lineages for Mhc-DRB1*03, -DRB1*04, -DRB1*10, and the loci of Mhc-DRB3, -DRB4, -DRB5, and -DRB6 predate speciation of man and rhesus monkey and were already present 25 million years ago.

Autoimmunity in non-human primates: the role of major histocompatibility complex and T cells, and implications for therapy.

Two autoimmune disease models were studied in rhesus monkeys: type II collagen-induced arthritis (CIA) and experimental allergic encephalomyelitis (EAE). Unrelated outbred animals were used in these studies. In both models disease resistant and susceptible individuals could be identified.

RFLP analysis of the rhesus monkey MHC class II DR subregion.

Restriction fragment length polymorphism (RFLP) analysis was performed on a panel of 39 serologically typed DR homozygous monkeys. DNA was digested with the restriction enzyme TaqI and hybridizations were carried out with a human leukocyte antigen (HLA)-DR beta 3'UT-specific probe. In addition a panel of 18 monkeys was analyzed comprising experimental autoimmune encephalomyelitis (EAE) susceptible and nonsusceptible animals.

Regulation of Fc receptor for IgE (CD23) and class II MHC antigen expression on Burkitt's lymphoma cell lines by human IL-4 and IFN-gamma.

The effect of rIL-4 on the expression of low affinity receptor for the Fc part of IgE (Fc epsilon R2/CD23) and class II MHC antigens on Burkitt's lymphoma (BL) cell lines was investigated. Some of the BL lines contained low percentages of CD23 and HLA-DQ-positive cells, but virtually all cells expressed HLA-DR. IL-4 induced CD23 and class II MHC Ag expression on 7 of 9 BL.

Two alleles detected for HLA-DZ alpha on the basis of a polymorphic restriction site in the third exon.

The restriction enzyme ApaI has been used to define Restriction Fragment Length Polymorphism (RFLP) within the DZ alpha gene. Digestion of genomic DNA of 96 individuals with ApaI reveals the existence of two different patterns. Both homozygous and heterozygous individuals were detected.