Saturday, August 6, 2011

Rheumatic fever pathogenesis and vaccine development

The pathogenesis of RF and RHD depends on several host factors that mediate a pathological autoimmune response triggered by a defensive response against S. pyogenes. Genetic predisposition is one of the factors contributing to the development of autoimmunity. Several genetic markers have been studied; however the most consistent associations were described for HLA class II genes. The HLADR7 allele is the one most frequently associated with the disease and seems to be related to the development of multiple valvular lesions in RHD patients. HLA class II molecules are expressed on the surface of antigen-presenting cells (APCs)—such as macrophages, dendritic cells, and B cells—and, together with bound peptide antigen, trigger the activation of T cells. The interaction of HLA molecules, antigenic peptide and T cell receptor (TCR) on the surface of T cells are crucial for the activation of the immune response.

The development of a protective immune response to prevent group A streptococci infections and RF/RHD still remains a question that requires a deep knowledge about the mechanism leading to pathological autoimmune reactions and how a vaccine could act to protect and avoid such effects. Both B and T immune responses are involved in the M protein and human tissue proteins through crossreactive reactions. There are evidences that the pathogenesis of rheumatic carditis is mediated by heart tissue crossreactive antibodies that cause an inflammation into the valve endothelium that facilitates T cells infiltration (Cunningham 2003). Heart infiltrating cells in both myocardium and valves produce inflammatory cytokines that enhance the autoimmune reactions. Additionally, the scarce numbers of cells producing the regulatory cytokine IL-4 in the valves are probably responsible for the progression and maintenance of chronic valve lesions (Guilherme et al. 2004). These heart-infiltrating T cells recognize peptides from both N-terminal region of M protein and heart-tissue derived proteins such as myosin and vimentin through molecular mimicry.

In the last 20 years ,there is a lot of challenges in order to develop a safe and efficacious vaccine against group A streptococci .These include:1-Such vaccine should induce protection against S. pyogenes without developing autoimmune reactions that could trigger RF ; antibodies directed against M protein for example could trigger both autoimmunity and protection (Cunningham 2000 review), 2- Vaccine strategies targeting N-terminal segment elicit type-specific antibodies and vaccines based on C-terminal region evoke broad serotype protective antibodies and therefore the latter vaccine may be more superior in protection against various stains of group A streptococci, 3- There are different serotypes of group A streptococci that produce RF ,some of which are known to be more rheumatogenic so the proposed vaccine has to include such variants. The vaccine coverage may not be the same in other continents, mainly in developing countries where there is little information regarding the distribution of M serotypes.

Two phase I clinical trials for preparing vaccine against group A streptococci are in progress and both are based on the N-terminal region. One of these studies evaluated the safety and immunogenicity of a recombinant group A streptococcal vaccine containing N-terminal M protein fragments from serotypes 1, 3, 5, 6, 19 and 24 and was tested in 28 healthy adult volunteers (Kotloff et al. 2004). The follow-up showed that the vaccine was well tolerated and evoked type specific opsonic antibodies against multiple serotypes of group A streptococcus without eliciting antibodies that cross-react with host tissues. Lately, a 26-valent vaccine has been constructed that includes 80–90% of serotypes that cause invasive infections or pharyngitis in North America (Shulman et al. 2004). This vaccine includes recombinant proteins that contain N-terminal peptides from streptococcal protective antigen and M proteins of 26 common pharyngitis, invasive, and/or rheumatogenic serotypes and was tested in 30 healthy adult volunteers (McNeil et al. 2005).

Because vaccine strategies targeting N-terminal segment elicit only type-specific antibodies while vaccines based on C-terminal region evoke broad serotype protective antibodies, a model was proposed and focused on the C terminal portion of M protein (Brandt et al. 2000; Medaglini et al. 2005). There are particular streptococcal strains involved with RF/RHD in some peoples with high incidence as in Australian and New Zealand aborigines, and, a vaccine model based on a combination of C- and N-terminal peptides from these strains is being assayed (Brandt et al. 2000). The most recent results from this group show that J14, a 29-mer peptide sequence which contains a conserved epitope from the C-terminal repeat of the streptococcal M protein, elicited protective opsonic antibodies against several GAS isolates. In vivo challenge experiments have also confirmed the protective efficacy of immunization with J14 peptide in different formulations (Vohra et al. 2005; Batzloff et al. 2005; Olive et al. 2005).

Differently from previously proposed models, a recently described approach searches for a protective B and T cell epitopes using a large panel of human samples of Brazilian population. A candidate vaccine segment was constructed and composed by both T and B epitopes with 16 identical amino acids. The advantage of such construction is the possibility to induce both T and B memory cells that will probably elicit a stronger protective immune response. In addition, the selected epitopes apparently were able to bind to any HLA class II molecules and activated T cells without HLA class II restriction as measured by proliferation assays. The reactivity of the selected peptides with human heart- infiltrating T cell lines (HIL) obtained from RHD patients was tested by proliferation assay and cytokine production. The preliminary results did not show crossreactivity indicating that the selected region could be a good candidate vaccine. The use of HIL from RHD patients was unique and reliable to control potential pathological autoimmune reactions due to the vaccine agent.

A similar construction was done by Good’s group in Australia. They identified a region on the C-terminal portion of M protein from prevalent strains of an Aboriginal endemic area first named P145 (Pruksakorn et al. 1994; Brandt et al. 2000) that resembles the B cell epitope identified in the previous study along with the Brazilian population. The same group proposed a new vaccine segment called J14 by modifying their first construction (P 145) due to the observed crossreactions with myosin and keratin (Hayman et al. 1997).

No comments: