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the majority of affected individuals the infection doesnot generate th


The Importance of Host Volume The studies undertaken to develop a humanizedM tuberculosisexperimental mouse models Given that granulomanecrosis was induced by a nonspecific inflammatoryprocessthe endo

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Document on Subject : "the majority of affected individuals the infection doesnot generate th"— Transcript:

1 the majority of affected individuals the
the majority of affected individuals the infection doesnot generate the slightest symptoms. Consequently,it isControl and Prevention in the USA recommended thedevelopment of a therapeutic vaccine against tuberculosisWithout doubt,a key aspect of M tuberculosisinfection,namely the appearance of the latent bacillus,characteristics. The appearance of this form of thebacillus has generated and continues to generate mostinterest on the part of tuberculosis researchers,to theextent that M tuberculosislatent tuberculosis infection.tuberculosisinfection is universally accepted does notalter the fact that it is an exaggeration of a biologicalcharacteristic that is extremely common inmicroorganisms. In fact,there are many microorganismswith an even greater capacity to persist for extendedperiods in host tissues. This applies principally to a largenumber of viruses,such as those of the herpes family.the case of bacteria,in all of the strains that it has beenpossible to study,researchers have observed theof nutrients when growing populations enter theIn addition,it has been demonstrated inall of these bacteria that the cells have a greater resistancetowards noxious environmental stimuli in that state.M tuberculosisconfirmed that it is not all that different genetically from,say,Escherichia coliThese approaches have also madeit possible to confirm that M tuberculosisgenerating an environmentally resistant form similar to aspore. At most,it has a highly complex hydrophobic cellwalland a very slow growth capacity. However,inessence,those are not characteristics that we need to fearin a bacterium. What,then,is the origin and significanceWithout doubt,interest in

2 this bacillus began withantibiotic treat
this bacillus began withantibiotic treatment using streptomycin in the 1950s,not be accounted for by resistance to the antibioticsSubsequently,towards the end of the 1970s,thegroup led by Mitchison,having designed a short-coursetreatment regimen for M tuberculosisfollowing the discovery of rifampicin,attempted toexplain why treatment of tuberculosis neverthelessneeded to be continued for 6 months. The action ofrifampicin,capable of destroying those bacilli thatactivate their metabolism for short periods of time,ledthat author to predict that a population of bacilli existedthat was either not metabolically active or had adrastically reduced metabolism. Those findings offeredan explanation for earlier experimental observationsregarding the capacity of M tuberculosisand confirmed clinical observationsregarding endogenous reactivation of tuberculosis.Visualizationof the Latent Bacillus:the Importance of Foamy MacrophagesIn the 1950s,the group of McCuneexperimental model in micethe Cornell modelthatbacillus. Following a short period of infection (around 2weeks) the animals were treated for 14 weeks withisoniazid and pyrazinamide,and it was confirmed thatno culturable bacteria could be isolated from thetissues. Three months later,or after 1 month ofhydrocortisone treatment,it was again possible toculture bacilli from the same tissues. It could beproposed,then,that during the period of time duringwhich the tissues remain sterile,the bacteria werepresent in a latent state. Those studies led variousauthors to address the different states of bacilli thatwere viable but not culturable,their recovery(technically,resuscitation),and the requirements for

3 resuscitation to occur.Again,many other
resuscitation to occur.Again,many other researchersworking with environmental bacteria have madenumerous,decisive contributions in this area that haveNumerous authors have also undertakenexperimental work to investigate the hypothesis thatvery low oxygen tension such as those which musttuberculosissubjected to hypoxic and even anaerobicconditions. At least 1 significant metabolic change wasidentified,the glyoxylate shunt,with at least 2outcomes:the generation of reduced NAD(nicotinamide adenine dinucleotide) to facilitateor simply to allow energy to beIan Orme,probably the living scientist who hasworked most extensively with experimental models oftuberculosis,challenged assumptions in the scientificcommunity 3 years ago in a discussion article entitledThe latent tuberculosis bacillus (Ill let you know if Iever meet one).Ormes paper was provocative,he put forth some veryinteresting theories. Firstly,he questioned therelationship between a positive tuberculin test and latentinfection. In doing so,he attacked one of the pillars ofimmunology,namely the presence of immunologicmemory,which in this case states that infection is notnecessary in order to present a reaction to the tuberculinAlthough defenders of the model havedemonstrated that the recovered bacteria continue to besensitive to isoniazid,Orme suggested that theirrecovery in a rich culture medium may lead to reversalof isoniazid resistance in order to be able to grow inArch Bronconeumol.2006;42(1):25-32 The Importance of Host Volume The studies undertaken to develop a humanizedM tuberculosisexperimental mouse models. Given that granulomanecrosis was induced by a nonspecific inflammatorypro

4 cess,the endotoxin had to be present in
cess,the endotoxin had to be present in the structureof the bacillus itself,the concentration of the endotoxinincreasing with the massive growth occurring at the endof the nonspecific response and provoking aphenomenon similar to the Shwartzman phenomenon.However,the marked increase in the concentration ofendotoxins as a result of substantial growth of thecase,why is the massive inflammatory reaction thatoccurs in granuloma necrosis not provoked in that host?The answer was found in the tolerance phenomenonthat the mouse must display in response to variousinfections. This is supported by simply observing itsvolume. It is clear that the mouse would never be ableto generate a tuberculous cavity like that generated inhumans,among other reasons because the averagevolume of a cavity is greater than the total volume of amouse. Therefore,it is not surprising that mice cantoleratea certain number of bacilli in their tissues; themouse is only able to generate a cleanresponse to themassive bacterial growth that could cause immediatedeath. In fact,studies undertaken in IFN-knockoutbegin until 3 weeks post infection.Another interesting finding is the dose of tuberculinnecessary to trigger the DTH in the infected host. This isaround 0.04 g in humans,but increases to 0.5 g inguinea pigs and 5 g in mice.greater tolerance of the latter animals to proteins derivedM tuberculosis,this observation may also reflectin guinea pigs infected with lowM tuberculosisin aerosols(unpublished data),we can assume that the number inhumans would be around 2 logThese findings suggest many things. Firstly,humansrespond much more effectively to M tuberculosisinfection.This is co

5 nsistent with the most widelyaccepted ep
nsistent with the most widelyaccepted epidemiologic data indicating that for every100 humans infected,only 10 develop the disease andIn mice,for every 100 infected animals,100 will die as aThese observations areillustrative of the type of effective immune responsethat can be developed against M tuberculosis.Inhumans,the response is a totally mixed T helper (Th):Th1 lymphocytes appear that are ableto activate infected macrophages and generatealongside a significant Th2 response that stimulates theproduction of antibodies,which are able to control theextracellular bacilli and prevent their spread,effective fibrosis of the granulomas through interleukin; finally,a marked inflammatory response generatesgranuloma necrosis,initially preventing spread of thebacillus. Unfortunately,development of the diseaseappears to be linked to a purely anatomic characteristicof humans. The presence of tissues with high oxygentensions,such as the apical lobes of the lung,favorslocal immunodepression and stimulates bacterialovergrowth.Thus,the development of tuberculosisin immunocompetent patients would be the result of theadaptation of the bacillus to a highly specific ecologicalniche,the fruit to centuries of evolution and,therefore,very difficult to resolve. We also have the tolerant response displayed by themouse,based mainly on the synthesis of IFN-,whichonly allows control of multiplying bacilli,leading to aspread of bacilli. Clearly,this type of response is notvery effective.These observations led us to conclude that theresponse generated to a therapeutic vaccine would haveto be mixed,able to prevent intracellular multiplicationof the bacillus,and also able to prev

6 ent extracellularspread. The low concent
ent extracellularspread. The low concentration of bacilli that can beexpected in the tissues of carriers led us also to thinkabout the requirement for such a vaccine to bemultiantigenic,in order to increase the possibility that anextremely low concentration of antigen (tolerated) wouldbe able to generate sufficient inflammatory response tomobilize immune cells to locate and destroy it.The Dynamic Nature of the Latent InfectionInvestigation of this process has always beenhindered by an important aspect of host physiology,namely continuous turnover of cells. It is estimated thatthe average life of an alveolar macrophage is,at most,Thus,it is quite clear that theto avoid drainage into the bronchial tree. It is relativelyclear that necrotic tissue represents a primary source ofthese bacilli. Pathologists generally have difficultywith granuloma necrosis indicative of being tuberculousIn our own group,we have difficulty inexperimental mouse model. As mentioned,there is nonecrotic tissue in this experimental model. However,asdescribed in the Cornell model,whereas prolongedantibiotic treatment (eg,14 weeks) with a combinationof pyrazinamide and isoniazid results in the almostcomplete elimination of lesions from the lungs,Arch Bronconeumol.2006;42(1):25-32 generation of new effector cells.This makes it ofparticular interest to undertake an immunotherapytreatment following chemotherapy in order to preventreactivation of the bacillus as a consequence of theshort-course chemotherapy) and the induction of localspecific immunodepression. Also for this reason,it isvery important to use an immunotherapy such as thatprovided by RUTI to be able to substantially reduc

7 e theperiod of chemotherapy by preventin
e theperiod of chemotherapy by preventing this means ofreactivation of latent bacilli (Figure).What is the Future for RUTI?The approach taken with RUTI came about inresponse to the questions that have been posed aboutthe pathophysiology of M tuberculosisinfection. Withthis approach,patients must complete a short course ofchemotherapy,of no more than a month,and then bevaccinated in order to destroy the latent bacilli that theycarry.To date,we have been able to demonstrate thatadministration of RUTI,made up of detoxifiedM tuberculosis well-balanced Th1/Th2/Th3 response and intenseantibody production that is highly effective in variousexperimental mouse modelsand even in the guineapig (unpublished data). We are currently interested inassessing its efficacy in a large animal,such as the pig,that is capable of developing an inflammatory responsevery similar to that of humans.The RUTI vaccine represents a significant advance inimmunotherapy for tuberculosis since it is the firstprototype that has demonstrated efficacy withoutdisplaying toxicity for the host. Although initiatives todesign new prototypes are currently underway,theRUTI vaccine is already being produced on a pilot scalefor use in clinical trials. If the advantage is not lost andthe necessary support is obtained,within a reasonableperiod of time (around 10 years) RUTI could representtuberculosiseffective and practical,and of course,to subsequently1.World Health Organization. Global Tuberculosis Control:2.American Thoracic Society. Targeted tuberculin testing and3.Centers for Disease Control and Prevention. Development of new4.Bloom DC. HSV LAT and neuronal survival. Int Rev Immunol.Arch Bronc

8 oneumol.2006;42(1):25-32 Possibility of
oneumol.2006;42(1):25-32 Possibility of a KochReaction in Necrotic Tissue Future Reservoir Foamy MacrophagesLocal Immunodepression Chemotherapy RUTI Possibility of Reactivation Possibility of Reactivation Temporal Progression 53.Wallace JG. The heat resistance of tubercle bacilli in the lungs of54.Ramachandra L, Noss E, Boom WH, Harding CV. Processing of55.Moreno E, Pizarro-Cerd J. Life and death of 56.Gross A, Terraza A, Ouahrani-Bettache S, Liautard JP, Dornand J.57.Cardona PJ, Gordillo S, Daz J, Tapia G, Amat I, Pallars A, et al.58.Scanga CA, Mohan VP, Yu K, Joseph H, Tanaka K, Chan J,59.Rhoades ER, Orme IM. Susceptibility of a panel of virulent strains60.Stumbles PA, McWilliam AS, Holt PG. Dendritic cells andStrober W, Bienenstock J, McGhee JR, editors. Mucosal61.Cardona PJ, Julin E, Valls X, Gordillo S, Muoz M, Luquin M,62.Cardona PJ, Amat I, Gordillo S, Arcos V, Guirado E, Daz J, et al.63.Bolin CA, Whipple DK, Khanna KV, Risdahl JM, Peterson PK,Arch Bronconeumol.2006;42(1):25-32 IntroductionIt is well known that Mycobacterium tuberculosisinfection currently affects around 2000 millionindividuals,a third of the worlds population. With sucha reservoir,control of tuberculosis would seem to be adifficult task to approach. The rates of morbidity andmortality are extremely high:it is estimated that 8million new cases of tuberculosis appear each year and2 million individuals will die as a consequence of the This work was supported by grants FIS 01/0644 and 01/3104 from the SpanishMinistry of Health, and by a grant from the Spanish Society of PulmonologyCorrespondence: Dr. P.J. Cardona.Unitat de Tuberculosi Experimental. Servei de Microbiologi