Effects of immunomodulators on the response induced by vaccines against autoimmune diseases

A promising treatment for T-cell-mediated autoimmune diseases is the induction of immune tolerance by modulating the immune response against self-antigens, an objective that may be achieved by vaccination. There are two main types of vaccines currently under development. The tolerogenic vaccines, composed of proteins formed by a cytokine fused to a self-antigen, which usually induce tolerance by eliminating the T-cells that are immune reactive against the self-antigen. The immunogenic vaccines, comprised of a self-antigen plus a sole Th2 adjuvant either free or conjugated, that alleviate autoimmunity by switching the immune response against the self-antigen, from a damaging pro-inflammatory Th1/Th17 to an anti-inflammatory Th2 immunity. Another type of vaccines is the DNA vaccines, where cells transiently express the self-antigen encoded by DNA, which induces a Th2 immunity. Actually, DNA vaccines can benefit from the presence of an adjuvant that elicits a systemic sole Th2 immunity to enhance the initially weak immune response characteristic of these vaccines. While in the tolerogenic vaccines, cytokines are the endogenous immunomodulators, in the immunogenic vaccines, the adjuvants are exogenous agents that elicit Th2 immunity with a production of anti-inflammatory cytokines and antibodies against the self-antigen. Because the commonly used Th2 adjuvant alum, fails to induce an effective immunity in the elderly population, it is unlikely that it would be widely used. Another Th2 adjuvant, the oil/water emulsions mixed with the antigen, while effective in vaccines against infectious agents, due to potential aldehydes in their formulation may be not suitable for autoimmune vaccines. A unique compound is glatiramer, which seems to be both a random polypeptide antigen and an immune modulator that biases the response to Th2 immunity. Its mechanism of action seems to implicate binding to MHC-II, which alters the outcome of T-cell signaling, leading to anergy. Glatiramer, while effective in the treatment of multiple sclerosis has not shown efficacy in other autoimmune diseases. An important new group of promising sole Th2 adjuvants are the fucosylated glycans, which by binding to DC-SIGN bias dendritic cells to Th2 immunity while inhibiting Th1/Th7 immunities. These glycans are similar to those produced by parasitic helminths to prevent inflammatory responses by mammalian hosts. A novel group of sole Th2 adjuvants are some plant-derived fucosylated triterpene glycosides, which share the immune modulatory properties from the fucosylated glycans. These glycosides have also an aldehyde group that delivers an alternative co-stimulatory signal to T-cells, averting the anergy associated with aging due to the loss of the CD28 receptor on T-cells. Hence, the development of vaccines to treat and/or prevent autoimmune conditions and some proteopathies, will significantly benefit from the availability of new sole Th2 adjuvants that while inducing an anti-inflammatory immunity, they do not abrogate pro-inflammatory Th1/Th17 immunities

Facing Alzheimer’s disease in the developing countries.

Aunque el incremento de casos de enfermedad de Alzheimer (EA) en los países desarrollados será limitado, en los países en desarrollo de América Latina, Asia y África será en el año 2050 tres veces el de los países desarrollados. Que ciertas correlaciones entre la EA y factores de riesgo válidas para los países desarrollados no son tan categóricas cuando se aplican a los países en desarrollo, sugiere diferencias en el desarrollo de fármacos para esta enfermedad. Es improbable que, debido al costo de las medicinas de los países industrializados, el tratamiento de la EA sea una prioridad en los países subdesarrollados; por lo tanto, una estrategia más efectiva sería el prevenir o retrasar esta enfermedad. De las opciones, la vacuna contra la EA es la más favorable a pesar de que todos los intentos para producirla han fracasado, resultado de productos desarrollados usando información insuficiente; lo que ha fomentado una opinión negativa de esta vacuna en los círculos científicos. Sin embargo, la información disponible revela que los antígenos de esas vacunas posiblemente indujeron una inmunidad perjudicial y que la respuesta inflamatoria estimulada por varias de esas vacunas agravó el inicio de EA. Además, debido al daño irreversible causado por la EA y la inmunosenescencia, es poco probable que las vacunas terapéuticas tengan valor práctico en el tratamiento de la EA en estado avanzado. Sin embargo, esta información provee bases sólidas para diseñar nuevas vacunas para prevenir o retardar esta enfermedad; información que ha sido ignorada y las vacunas para prevenir la EA, de hecho descartadas. No obstante, ahora hay un mejor conocimiento de los inmunógenos necesarios para inducir una inmunidad protectora y de los adyuvantes requeridos para estimular la producción de anticuerpos protectores e inhibir la inmunidad inflamatoria perjudicial. Considerando las opciones limitadas que tienen los países en desarrollo para controlar la epidemia de EA, sería razonable si estos países colaboraran y usaran los conocimientos disponibles para desarrollar vacunas para prevenir/retrasar la EA. Un avance que produciría beneficios médicos y económicos para América Latina y otras regiones del mundo

Alzheimer’s disease: Toward the rational design of an effective vaccine.

The promising clinical results with the human monoclonal antibodies aducanumab and solanezumab targeting β-amyloidin Alzheimer’s disease treatment, confirm both the amyloid cascade hypothesis and protective natural immunity, while strengthening the immunotherapeutic approach. That aducanumab recognizes a conformational epitope formed by oligomers emphasizes the need for whole β-amyloid, not just its B-cell epitopes as have been the norm to avoid pro-inflammatory Th1-reactions. That truncated β-amyloid having N-terminal pyroglutamate is present only in diseased brain simplies a new useful vaccine antigen. Another relevant antigen is the tau protein, which shows a close association and cooperativity with β-amyloid in exacerbating this disease. Hence, effective vaccines may be polyvalent, presenting to the immune system a number of antigens relevant to induce an immune response to prevent or slowdown the onset of this disease. The presence of both B and T cell epitopes in the antigens, require a sole Th2 immunity to avert brain inflammation; a task that cannot be attain with adjuvants that under any conditions induce Th1and/or Th17immunities.Hence, new vaccine adjuvants are need to safely induce Th2 while inhibiting Th1 immunity, an objective that can be achieved with certain fucosylated glycans or triterpene glycosides, which apparently bind to the DC-SIGN lectin on dendritic cells polarizing the immune response toward Th2 immunity. Because the triterpene glycosides have the pharmacophore needed to co-stimulate T cells, they may ameliorate the T-cell anergy associated with immunosenescence and responsible for poor vaccine efficacy in theelderly population, a critical issue for an Alzheimer’s vaccine

The Microbiota, Immunoregulation, and Mental Health: Implications for Public Health

The hygiene or "Old Friends" hypothesis proposes that the epidemic of inflammatory disease in modern urban societies stems at least in part from reduced exposure to microbes that normally prime mammalian immunoregulatory circuits and suppress inappropriate inflammation. Such diseases include but are not limited to allergies and asthma; we and others have proposed that the markedly reduced exposure to these Old Friends in modern urban societies may also increase vulnerability to neurodevelopmental disorders and stress-related psychiatric disorders, such as anxiety and affective disorders, where data are emerging in support of inflammation as a risk factor. Here, we review recent advances in our understanding of the potential for Old Friends, including environmental microbial inputs, to modify risk for inflammatory disease, with a focus on neurodevelopmental and psychiatric conditions. We highlight potential mechanisms, involving bacterially derived metabolites, bacterial antigens, and helminthic antigens, through which these inputs promote immunoregulation. Though findings are encouraging, significant human subjects' research is required to evaluate the potential impact of Old Friends, including environmental microbial inputs, on biological signatures and clinically meaningful mental health prevention and intervention outcomes