BRPI1003830A2 - use and formulations of the immunoprophylactic antigen of the leishmania amazonensis promastigote flagellate fraction immunomodulated with colmett guerin (bcg) against canine visceral leishmaniasis (lvc) - Google Patents
use and formulations of the immunoprophylactic antigen of the leishmania amazonensis promastigote flagellate fraction immunomodulated with colmett guerin (bcg) against canine visceral leishmaniasis (lvc) Download PDFInfo
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Abstract
USO E FORMULAÇÕES DO ANTÍGENO IMUNOPROFILÁTICO DA FRAÇçO FLAGELAR DE PROMASTIGOTA DE LEISHMANIA AMAZONENSIS IMUNOMODULADA COM BACILO COLMETT GUERIN (BCG) CONTRA LEISHMANIOSE VISCERAL CANINA (LVC). A presente invenção refere-se ao uso e formulações do antígeno imunoprofilático de fração flagelar de promastigota de Leishmania amazonensis imunomodulada com bacilo Colmett Guerin (BCG) contra leishmaniose visceral canina (LVC), o que favorece o desenvolvimento de eventos imunológicos específicos capazes de combater o parasita durante os estágios iniciais da infecção. O uso dessa fração favorece a discriminação entre cães vacinados de cães doentes, por se tratar de um antígeno heterólogo, já que a L. amazonensis não pertence ao "complexo donovani" onde estão inseridos os subgêneros responsáveis pela leishmaniose visceral. Assim, quando os animais forem submetidos ao exame sorológico recomendado pela Fundação Nacional de Saúde, órgáo do Ministério da Saúde responsável para o diagnóstico da LV, aqueles imunizados com fração flagelar de L. amazonensis aparecerão negativo ao exame o que permitirá diferenciar animais não infectados de animais infectados com L.(L) chagasi agente responsável pela LV.USE AND FORMULATIONS OF THE IMMUNOPROPHILLATIC ANTIGEN OF THE FLAGELAR FRACTION OF IMMUNOMODULATED AMAZONENSIS AMAZONENSIS PROMASTITUTE WITH COLMETT GUERIN (BCG) BACYL AGAINST CANINE VISCERAL LEISHMANIASIS (LVC). The present invention relates to the use and formulations of the Colmett Guerin Bacillus Immunododulated Leishmania amazonensis (BCG) promastigote flagellar fraction immunoprophylactic antigen against canine visceral leishmaniasis (LVC), which favors the development of specific immunological events capable of counteracting the disease. parasite during the early stages of infection. The use of this fraction favors the discrimination between vaccinated dogs of sick dogs, because it is a heterologous antigen, since L. amazonensis does not belong to the "donovani complex" where the subgenera responsible for visceral leishmaniasis are inserted. Thus, when the animals are submitted to the serological examination recommended by the National Health Foundation, an organ of the Ministry of Health responsible for the diagnosis of VL, those immunized with L. amazonensis flagellar fraction will appear negative for the examination, which will allow to differentiate uninfected animals from animals infected with L. (L) chagasi agent responsible for VL.
Description
"USO E FORMULAÇÕES DO ANTÍGENO IMUNOPROFILÁTICO DA FRAÇÃO FLAGELAR DE PROMASTIGOTA DE LEISHMANIA AMAZONENSIS IMUNOMODULADA COM BACILO COLMETT GUERIN (BCG) CONTRA LEISHMANIOSE VISCERAL CANINA (LVC)". CAMPO DA INVENÇÃO"USE AND FORMULATIONS OF THE IMMUNOPROPHILLATIVE ANTIGEN OF THE FLAGELAR FRACTION OF LEISHMANIA AMAZONENSIS PROMASTITUTE IMMUNOMODULATED WITH COLMETT GUERIN (BCG) BACYL AGAINST CANINE VISCERAL LEISHMANIASIS (LVC)". FIELD OF INVENTION
A presente invenção refere-se ao uso e formulações do antígeno imunoprofilático de fração flagelar de promastigota de Leishmania amazonensis imunomodulada com bacilo Colmett Guerin (BCG) contra Ieishmaniose visceral canina (LVC) atuando assim, como um bloqueador na cadeia de transmissão da Ieishmaniose visceral (LV).The present invention relates to the use and formulations of the Colmett Guerin Bacillus Immunododulated Lemamania amazonensis (BCG) promastigote flagellate fraction immunoprophylactic antigen against canine visceral leishmaniasis (LVC) thus acting as a blocker in the visceral leishmaniasis transmission chain ( LV).
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Mais especificamente a invenção refere-se ao uso do antígeno de fração flagelar de promastigota de' L. amazonensis no éstímulo de respostas celulares Iinfoproliferativas capazes de gerar uma reação limunoprotetora, tornando-se assim, um potencial candidato a vacina.More specifically the invention relates to the use of the L. amazonensis promastigote flagellate fraction antigen in stimulating lymphoproliferative cell responses capable of generating a limonoprotective reaction, thus becoming a potential vaccine candidate.
FUNDAMENTOS DA INVENÇÃOBACKGROUND OF THE INVENTION
A Ieishmaniose visceral (LV) também conhecida como calazar, é uma enfermidade parasitária, de caráter zoonótico e de distribuição mundial, causada por protozoários do gênero Leishmania e transmitida principalmente durante a picada do inseto vetor flebotomineos. A LV tem sido notificada nos cães e no homem, em vários estados brasileiros, sendo considerada uma endemia. No Brasil LV é causada pelo :parasito \Leishmania (L) chagasi que causa alterações patológicas, e é responsável por altos índices de morbidade e mortalidade sendo a LV considerada um importante problema de saúde pública e tendo o cão como principal reservatório da doença para o homem. Aproximadamente 50 a 60% dos cães infectados são assintomáticos, oVisceral leishmaniasis (VL), also known as calazar, is a parasitic disease of zoonotic character and worldwide distribution, caused by protozoa of the genus Leishmania and transmitted mainly during the bite of the phlebotomine insect vector. VL has been reported in dogs and men in several Brazilian states and is considered an endemic disease. In Brazil VL is caused by: parasite \ Leishmania (L) chagasi that causes pathological changes, and is responsible for high morbidity and mortality rates. VL is considered an important public health problem and the dog is the main reservoir of the disease for the dog. man. Approximately 50 to 60% of infected dogs are asymptomatic.
que sugere a existência de animais com a infecção na população e esses cães assintomáticos podem apresentar grande quantidade de parasitos na pele, o que favorece a infecção do inseto vetor, permanecendo um elo no ciclo biológico da doença.suggesting the existence of animals with the infection in the population and these asymptomatic dogs may present large amount of parasites in the skin, which favors the infection of the vector insect, remaining a link in the biological cycle of the disease.
A Ieishmaniose visceral canina (LVC) no Brasil encontra-se em expansão e urbanização e tendo como determinante epidemiológico desse processo os seguintes fatores: a movimentação de pessoas e animais domésticos de regiões endêmicas para áreas onde o inseto transmissor já se encontra adaptado e o desmatamento desordenado com conseqüente desequilíbrio dos ecossistemas. A transmissão da doença canina tem ocorrido de formas peri-urbana e urbana muito próxima ao centro de grandes cidades brasileiras como, Teresina, São Luis, Fortaleza, Aracaju, João Pessoa, Rio de Janeiro, Corumbá, Santarém e Belo Horizonte. 1Canine visceral leishmaniasis (CVL) in Brazil is expanding and urbanizing, and its epidemiological determinant is the following factors: the movement of people and domestic animals from endemic regions to areas where the transmitting insect is already adapted and deforestation disordered with consequent imbalance of ecosystems. Canine disease transmission has occurred in peri-urban and urban forms very close to the center of large Brazilian cities such as Teresina, Sao Luis, Fortaleza, Aracaju, Joao Pessoa, Rio de Janeiro, Corumbá, Santarém and Belo Horizonte. 1
Atualmente, vários grupos de pesquisadores vêm trabalhando no desenvolvimento de vacinas contra Ieishmaniose visceral e entre esses potenciais candidatos a vacina tem-se as vacinas de primeira geração que são constituídos por parasitos mortos tais como, L. mexicana, L. brasiliensis, L. major e L. amazonensis, podendo ser associados ou não com adjuvantes ou imunomoduladores como o BCG. ( . tSeveral groups of researchers are currently working on the development of visceral yeishmaniasis vaccines, and among these potential vaccine candidates are first generation vaccines that consist of dead parasites such as L. mexicana, L. brasiliensis, L. major. and L. amazonensis, which may or may not be associated with adjuvants or immunomodulators such as BCG. (. t
Toda medida terapêutica tem como finalidade a recuperação de indivíduos doentes e/ou infectados com o propósito do controle profilático da infecção. No entanto, em se tratando da LVC as tentativas de tratamentos comAll therapeutic measures aim to recover sick and / or infected individuals for the purpose of prophylactic infection control. However, in the case of CVL, attempts to treat
de drogas comercialmente utilizadas com, eficácia em humanos, não têm obtidocommercially used drugs that have been effective in humans have not obtained
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êxito na terapêutica em cães. Além do mais, a Organização Mundial da Saúde (OMS) recomenda o diagnóstico precoce e tratamento dos casos humanos e sacrifícios dos cães soropositivos como medida de controle da doença. Entretanto, o sacrifício dos cães soropositivos-é questionável em relação ao controle da doença. Dessa forma, o desenvolvimento de vacinas canina surge como uma estratégia importante no controle da doença.successful therapy in dogs. In addition, the World Health Organization (WHO) recommends early diagnosis and treatment of human cases and sacrifices of seropositive dogs as a disease control measure. However, the sacrifice of seropositive dogs is questionable in relation to disease control. Thus, the development of canine vaccines emerges as an important strategy in disease control.
A avaliação do curso da infecção, pssim como da eficácia de preparações vacinais em modelos experimentais, constitui-se em um dos pilares da aquisição de conhecimento (para o desenvolvimento de vacinas contra a leishmaniose. Em camundongos, a resistência à infecção por espéciesThe evaluation of the course of infection, as well as the efficacy of vaccine preparations in experimental models, is one of the pillars of knowledge acquisition (for the development of vaccines against leishmaniasis. In mice, resistance to infection by species
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I : ; 1 3/6; de Leishmania que causam LV relaciona-se ao desenvolvimento de resposta celular do tipo Th1, com produção de IL-12 e IFN-γ.I:; 1 3/6; of Leishmania that cause VL is related to the development of Th1-type cellular response, with IL-12 and IFN-γ production.
Protocolos de imunização com a fração flagelar de L. (L.) amazonensis visando à indução de resposta celular em Ieishmaniose visceral murina, vem sendo utilizados por Do Valle et al. (2007). Dentro desse enfoque, tem sido investigada a imunogenicidade de frações subcelulares de tripanosomatídeos e algumas têm apresentado bom potencial como antígenos protetores em modelo murino.Immunization protocols with the flagellar fraction of L. (L.) amazonensis aiming at induction of cellular response in murine visceral leishmaniasis have been used by Do Valle et al. (2007). Within this approach, the immunogenicity of trypanosomatid subcellular fractions has been investigated and some have shown good potential as protective antigens in a murine model.
Os eventos imunológicos associados à imunoproteção e patologia na LVC mostraram, de acordo com as últimas pesquisas, que os padrões de imunidade protetora para l Leishmania em cães são semelhantes àqueles observados em modelos de Ieishmaniose experimental murina e em humanos. O conhecimento destas informações representa uma base importante para a busca de antígenos capazes de intervir no sistema imunológico do cão, favorecendo o desenvolvimento de eventos imunológicos específicos capazes de combater o parasita durante os estágips iniciais da infecção.Immunological events associated with immunoprotection and pathology in CVL have shown, according to the latest research, that the protective immunity patterns for l Leishmania in dogs are similar to those observed in murine experimental human leishmaniasis models. Knowledge of this information represents an important basis for the search for antigens capable of intervening in the dog's immune system, favoring the development of specific immunological events capable of fighting the parasite during the early stages of infection.
Alguns estudos têm sido realizados com o intuito de desenvolver uma vacina contra a LVC, porém, estes apresentaram resultados controversos ou pouco conclusivos, o que tem incentivado a busca de novos imunógenos que possam proporcionar uma intervenção vacinai eficaz para o controle dessaSome studies have been conducted with the intention of developing a vaccine against the CVL, but these have presented controversial or inconclusive results, which has encouraged the search for new immunogens that can provide an effective vaccine intervention to control this vaccine.
doença. ·, .disease. ·,.
Estudos empregando candidatos à vacina, de primeira geração, para Ieishmaniose têm mostrado alguns resultados importantes. Na Europa, foi desenvolvida uma vacina, constituída de uma preparação parcialmenteStudies employing first-generation vaccine candidates for leishmaniasis have shown some important results. In Europe, a vaccine has been developed, consisting of a preparation partially
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purificada e Iiofilizada derivada de L. infantum, que; quando aplicada em modelo experimental murino foi capaz de proteger os camundongos contra um desafio com L. mexicana e L. major. Entretanto, quando, avaliada experimentalmente em cães, foi observada apenas uma elevada produção de anticorpos incapazes de controlar a infecção. No entanto, estudos demonstram que a fração microssomal de formas promastigotas de L. (L.) amazonensis é capaz de induzir proteção em camundongos albinos quando BCG é empregado como imunomodulador (Gonçalves da Costa et al., 1988).purified and lyophilized derived from L. infantum, which; when applied in a murine experimental model it was able to protect the mice against a challenge with L. mexicana and L. major. However, when evaluated experimentally in dogs, only a high production of antibodies unable to control the infection was observed. However, studies show that the microsomal fraction of promastigote forms of L. (L.) amazonensis is able to induce protection in albino mice when BCG is employed as an immunomodulator (Gonçalves da Costa et al., 1988).
No Brasil são inúmeros os trabalhos que buscam o desenvolvimento de uma vacina contra a LVC, como é apresentado nas patentes PI0503187-7 A2, PI0601225-6 A2 e PI0603490-0 A2. Dentre os vários estudos destacam-se os realizados pelo grupo de Ieishmaniose do Departamento de Parasitologia da UFMG. Eles desenvolveram uma vacina composta por antígeno de promastigotas sonicadas. Este estudo foi levado a campo e foram realizados dois ensaios vacinais em população de cães no município de Montes Claros (MG), onde a LV é endêmica. Nesse estudo de campo os resultados do teste de eficácia de vacinação não demonstraram o estabelecimento de mecanismos protetores contra a infecção por Leishmania na população vacinada em relação ao grupo controle.In Brazil there are numerous studies that seek the development of a vaccine against CVL, as presented in the patents PI0503187-7 A2, PI0601225-6 A2 and PI0603490-0 A2. Among the various studies, we highlight those carried out by the Ieishmaniasis group of the UFMG Department of Parasitology. They developed a vaccine made up of sonicated promastigote antigen. This study was carried out in the field and two vaccine trials were performed in a dog population in the municipality of Montes Claros (MG), where VL is endemic. In this field study, the results of the vaccination efficacy test did not demonstrate the establishment of protective mechanisms against Leishmania infection in the vaccinated population in relation to the control group.
Outros estudos com vacina contra LVC foram desenvolvidos, tais como, o do grupo de pesquisadores da UFRJ, usando frações ou sub-frações de promastigotas ou amastigotas de Leishmania denominadas fucose mannose Iigand (FML) e saponina e mais recentemente pesquisadores da UFMG com vacina recombinante contendo o antígeno recombinante A2. No entanto, várias restrições para o uso deste imunobiológico têm sido apresentadas, principalmente à escassez de fundamentação científica acerca das bases celulares e moleculares da imunidade p;rqtetora pós-vacinal.Other studies of the vaccine against the CVL have been developed, such as the UFRJ research group, using fractions or sub-fractions of Leishmania promastigotes or amastigotes called fucose mannose Iigand (FML) and saponin and more recently UFMG researchers with recombinant vaccine. containing the recombinant antigen A2. However, several restrictions for the use of this immunobiological have been presented, mainly due to the scarcity of scientific basis regarding the cellular and molecular bases of post-vaccine immunity.
BREVE DESCRIÇÃO DA INVENÇÃO 1BRIEF DESCRIPTION OF THE INVENTION 1
A presente invenção refere-se à utilização de frações flagelares de promastigota de L. amazonensis, sendo que, essas frações são capazes de induzir proteção contra LVC quando BCG é empregado como imunomodulador, o que foi observado em nossos estudos com cães de área endêmica. Constatou-se que após 12 meses do processo imunoprofilático com a fração flagelar imunomodulada com BCG, os: cães apresentavam-se negativos a sorologia e aos testes imuno-histoquímicos. A vantagem do uso dessa fração em nosso invento é principalmente por se tratar de um antígeno heterólogo oThe present invention relates to the use of L. amazonensis promastigote flagellar fractions, and these fractions are capable of inducing protection against CVL when BCG is used as an immunomodulator, which was observed in our studies with endemic dogs. It was found that after 12 months of the immunoprophylactic process with the BCG immunomodulated flagellar fraction, the dogs were negative for serology and immunohistochemical tests. The advantage of using this fraction in our invention is mainly because it is a heterologous antigen or
ι que favorece a discriminação entre cães vacinados de cães doentes, já que a L amazonensis não pertence ao "complexo donovani" onde estão inseridos os subgêneros responsáveis pela Ieishmaniose .visceral. Ressalta-se ainda a capacidade imunogênica que a fração flagelar de L. amazonensis apresenta por induzir um estado de imunidade celular duradoura com resposta imunológica mais efetiva contra a LVC proporcionando assim um grau de proteção maior com resposta mais prolongada em relação aos antígenos constituídos por frações homólogasIt favors the discrimination between vaccinated dogs and sick dogs, since L amazonensis does not belong to the "donovani complex" where the subgenera responsible for the visceral leishmaniasis are inserted. Also noteworthy is the immunogenic capacity of the L. amazonensis flagellar fraction by inducing a lasting cellular immunity state with a more effective immune response against the CVL, thus providing a greater degree of protection with a longer response to antigens constituted by fractions. counterparts
DESCRIÇÃO DETALHADA DA INVENÇÃODETAILED DESCRIPTION OF THE INVENTION
"A presente invenção refere-se ao uso e formulações do antígeno imunoprofilático de fração flagelar de promastigota. de Leishmania amazonensis imunomodulada com bacilo Colmett Guerin (BCG): contra Ieishmaniose visceral canina (LVC)1 sendo administrado em I três doses. A primeira dose a ser administrada é a do imunomodulador, BCG1 na quantidade de 1x105 células por via-intradérmica; após 21 dias -administra-se uma segunda dose contendo apenas a fração flagelar de promastigota de L. amazonensis na quantidade de 50pg por via subcutânea. 21 dias após a segunda dose administra-se a terceira dose contendo novamente e somente a fração flagelar de promastigota de L"The present invention relates to the use and formulations of the Colmett Guerin Bacillus Immunododulated Promastigote Flagella Fraction Immunoprophylactic Antigen of the Canine Visceral Ieishmaniasis (LVC) 1 being administered in three doses. The immunomodulator BCG1 is intradermally administered with 1x10 5 cells, and after 21 days a second dose containing only the 50 amazonam subcutaneous flagellate promastigote is administered 21 days later. after the second dose the third dose is administered containing again and only the flagellar promastigote fraction of L
I SI S
amazonensis na quantidade 5(^g por via subcutânea, completando assim as três doses do complexo imunoprofilático comppsto pelo BCG e a fração flagelar.amazonensis in quantity 5 (μg subcutaneously), thus completing the three doses of the BCG-composed immunoprophylactic complex and the flagellar fraction.
A presente invenção tem como objetivo induzir um estado de imunidade celular duradoura com resposta imunológica, mais efetiva contra a LVC favorecendo assim, o desenvolvimento de eventos imunológicos específicos capazes de combater o parasita durante os estágios iniciais da infecção. A vantagem do uso dessa fração em nosso invento é principalmente por se tratar de um antígeno heterólogo o que f^vorece| a discriminação entre cães vacinados de cães doentes, já que a L. amazonensis não pertence ao "complexo donovani" onde estão inseridos os pubgêneros responsáveis pela Ieishmaniose visceral. Assim, quando os, animais forem submetidos ao exame sorológico recomendado pela Fundação Nacional de Saúde, órgão do Ministério da Saúde responsável para o diagnóstico da LV1 aqueles imunizados com fração flagelar de L. amazonensis aparecerão negativo ao exame o que permitirá diferenciar animais não infectados de animais infectados com L(L) chagasi agente responsável pela LV.The present invention aims to induce a more effective immune response lasting cellular immunity state against the CVL thus favoring the development of specific immunological events capable of combating the parasite during the early stages of infection. The advantage of using this fraction in our invention is mainly because it is a heterologous antigen which favors | the discrimination between vaccinated dogs and sick dogs, since L. amazonensis does not belong to the "donovani complex" where the visceral leishmaniasis are inserted. Thus, when the animals are submitted to the serological examination recommended by the National Health Foundation, an organ of the Ministry of Health responsible for the diagnosis of LV1, those immunized with L. amazonensis flagellar fraction will appear negative for the examination, which will allow to differentiate uninfected animals from animals infected with L (L) chagasi agent responsible for VL.
Claims (6)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| BRPI1003830 BRPI1003830A2 (en) | 2010-10-21 | 2010-10-21 | use and formulations of the immunoprophylactic antigen of the leishmania amazonensis promastigote flagellate fraction immunomodulated with colmett guerin (bcg) against canine visceral leishmaniasis (lvc) |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| BRPI1003830 BRPI1003830A2 (en) | 2010-10-21 | 2010-10-21 | use and formulations of the immunoprophylactic antigen of the leishmania amazonensis promastigote flagellate fraction immunomodulated with colmett guerin (bcg) against canine visceral leishmaniasis (lvc) |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| BRPI1003830A2 true BRPI1003830A2 (en) | 2013-02-26 |
Family
ID=47739530
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| BRPI1003830 BRPI1003830A2 (en) | 2010-10-21 | 2010-10-21 | use and formulations of the immunoprophylactic antigen of the leishmania amazonensis promastigote flagellate fraction immunomodulated with colmett guerin (bcg) against canine visceral leishmaniasis (lvc) |
Country Status (1)
| Country | Link |
|---|---|
| BR (1) | BRPI1003830A2 (en) |
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2010
- 2010-10-21 BR BRPI1003830 patent/BRPI1003830A2/en not_active Application Discontinuation
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