Killing of Targets by CD8+ T Cells in the Mouse Spleen Follows the Law of Mass Action

It has been difficult to correlate the quality of CD8 T cell responses with protection against viral infections. To investigate the relationship between efficacy and magnitude of T cell responses, we quantify the rate at which individual CD8 effector and memory T cells kill target cells in the mouse spleen. Using mathematical modeling, we analyze recent data on the loss of target cells pulsed with three different peptides from the mouse lymphocytic choriomeningitis virus (LCMV) in mouse spleens with varying numbers of epitope-specific CD8 T cells. We find that the killing of targets follows the law of mass-action, i.e., the death rate of individual target cells remains proportional to the frequency (or the total number) of specific CD8 T cells in the spleen despite the fact that effector cell densities and effector to target ratios vary about a 1000-fold. The killing rate of LCMV-specific CD8 T cells is largely independent of T cell specificity and differentiation stage. Our results thus allow one to calculate the critical T cell concentration at which growth of a virus with a given replication rate can be prevented from the start of infection by memory CD8 T cell response

Induction of Heme Oxygenase-1 Can Halt and Even Reverse Renal Tubule-Interstitial Fibrosis

Background: The tubule-interstitial fibrosis is the hallmark of progressive renal disease and is strongly associated with inflammation of this compartment. Heme-oxygenase-1 (HO-1) is a cytoprotective molecule that has been shown to be beneficial in various models of renal injury. However, the role of HO-1 in reversing an established renal scar has not yet been addressed. Aim: We explored the ability of HO-1 to halt and reverse the establishment of fibrosis in an experimental model of chronic renal disease. Methods: Sprague-Dawley male rats were subjected to unilateral ureteral obstruction (UUO) and divided into two groups: non-treated and Hemin-treated. To study the prevention of fibrosis, animals were pre-treated with Hemin at days -2 and -1 prior to UUO. To investigate whether HO-1 could reverse established fibrosis, Hemin therapy was given at days 6 and 7 post-surgery. After 7 and/or 14 days, animals were sacrificed and blood, urine and kidney tissue samples were collected for analyses. Renal function was determined by assessing the serum creatinine, inulin clearance, proteinuria/creatininuria ratio and extent of albuminuria. Arterial blood pressure was measured and fibrosis was quantified by Picrosirius staining. Gene and protein expression of pro-inflammatory and pro-fibrotic molecules, as well as HO-1 were performed. Results: Pre-treatment with Hemin upregulated HO-1 expression and significantly reduced proteinuria, albuminuria, inflammation and pro-fibrotic protein and gene expressions in animals subjected to UUO. Interestingly, the delayed treatment with Hemin was also able to reduce renal dysfunction and to decrease the expression of pro-inflammatory molecules, all in association with significantly reduced levels of fibrosis-related molecules and collagen deposition. Finally, TGF-beta protein production was significantly lower in Hemin-treated animals. Conclusion: Treatment with Hemin was able both to prevent the progression of fibrosis and to reverse an established renal scar. Modulation of inflammation appears to be the major mechanism behind HO-1 cytoprotection.Fundacao de Amparo Pesquisa do Estado de Sao Paulo-FAPESP[07/07139-3]Coordenaco de Aperfeioamento de Pessoal de Nivel Superior-CAPESInstituto Nacional de Ciencia e Tecnologia de Complexos Fluidos (INCT)Conselho Nacional de Desenvolvimento Cientifico e Tecnologico-CNP

Rabies chemiotherapy

Quarante-cinq substances antivirales ont été injectées à la souris enragée dans des conditions telles qu elles se trouvaient en contact avec les cellules infectées par le virus rabique, c’est-à-dire par voie intramusculaire proche du site d’inoculation et par voie intracérébrale quand le virus atteint le cerveau. Des hétéropolyanions (plus précisément le HPA 39) inhibent le développement de l’infection lorsqu’ils sont injectés par voie intramusculaire, tôt au cours de l’infection. Toutes les souris traitées survivantes ont des anticorps rabiques. Aucune preuve d’une éventuelle multiplication virale n’a été trouvée dans les cerveaux de ces souris. Cet hétéropolyanion a été administré à des renards enragés. L’efficacité de cette substance a été évidente si l’on considère soit l’augmentation du délai de mortalité, soit la survie de certains renards. Ces résultats sur le traitement rabique à l’aide du HPA suggèrent qu’une chimio thérapie pourrait être envisageable dans le cas où le traitement vaccinal ne peut être réalisé.Forty five drugs were administrated to rabies infected mice in such conditions that they could be in contact with the infected cells i.e. intramuscularly at the site of virus inoculation and intracerebrally when the virus reached the central nervous system, brain more precisely. Heteropolyanions, (more precisely HPA 39) prevented the development of clinical infection when injected intramuscularly early by I.M. All the treated surviving mice, developed rabies neutralizing antibodies. No proof was found of viral multiplication in their brains. This heteropolyanion was administrated to rabies infected foxes. The efficacy of this compound was evident considering the prolongation of mean survival time and number of survivors. These data on HPA treatment suggest that chemotherapy might be worthwhile when vaccine treatment is impossible

Development of animal recombinant DNA vaccine and its efficacy in foxes.

Rabies is prevalent in most parts of the world. An extensive reservoir of the disease is present in the population of wild animals. The fox in particular is a major vector of the disease in North America and Europe. Although attempts to control rabies by vaccination of wild carnivores with attenuated rabies virus have met with some success, this approach remains controversial. The potential of a recombinant vaccinia virus expressing the rabies glycoprotein for the protection of foxes against rabies was examined. Both the parental (wild-type) and recombinant viruses were found to be innocuous to foxes. Inoculation of live recombinant virus via the subcutaneous, intradermal, or oral routes uniformly elicited high titers of neutralizing antibodies, and animals that received 10(8) plaque-forming units of the recombinant virus in bait resisted severe challenge with live rabies virus