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European Tacrolimus Multicenter Atopic Dermatitis Study Group buy phenytoin 100 mg on line. Onset of action of pimecrolimus cream 1% in the treatment of atopic eczema in infants order phenytoin 100mg on line. SDZ ASM 981: an emerging safe and effective treatment for atopic dermatitis buy phenytoin 100 mg amex. Staphylococcus colonization in atopic dermatitis treated with fluticasone or tacrolimus with or without antibiotics. Schnopp C, Remling R, Mohrenschlager M, Weigl L, Ring J, Abeck D. Topical tacrolimus (FK506) and mometasone furoate in treatment of dyshidrotic palmar eczema: a randomized, observer-blinded trial. Ashcroft D, Chen L-C, Garside R, Stein K, Williams H. The effectiveness and cost-effectiveness of pimecrolimus and tacrolimus for atopic eczema: a systematic review and economic evaluation. Topical calcineurin inhibitors Page 46 of 74 Final Report Drug Effectiveness Review Project 32. Iskedjian M, Piwko C, Shear NH, Langley RGB, Einarson TR. 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This may occur because dominant CTLs clear infected cells and associated subdominant epitopes too quickly for the weak CTL stimulation by subdominant epitopestogenerate a strong CTL response (Nowak et al buy phenytoin 100 mg without prescription. Alternatively order 100mg phenytoin visa, the CTLs may compete directly at antigen-presenting cells for stimulation discount phenytoin 100 mg otc. Finally, the dominant CTLs may be able to suppress subdominant clones by compe- tition for resources or by expressing suppressive cytokines. On the whole, the evidence supports the second explanation, in which dominant clones suppress subdominant clones. The strain WE stimulated a dominant response against the epitope NP118−126,whereasthestrain ESC lacked this dominant epi- tope and stimulated response against various minor epitopes including GP283−291. ClassIMHCpresents the minor epitopes in WE-infected cells, but does not stimulate significant CTL response. Importantly, CTLs spe- cific for the subdominant epitope GP283−291 lyse WE and ESC target cells to the same extent, suggesting thatthesubdominant epitope is pre- sented effectively equally on the surfaces of WE and ESC cells. Thus, the strength of the CTL response is not caused by numerical differences in epitope presentation on cell surfaces. The NP118−126-specific CTLs do not directly suppress CTLs against mi- nor epitopes, because coinfection by WE and ESC produces a significant CTL response against both NP118−126 and GP283−291,suggesting that ESC generates a CTL response against GP283−291 without interference by the WE-induced CTLs against NP118−126. Expansion of the dominant CTL clone against NP118−126 and clear- ance of WE infection occurred more rapidly than did expansion of the subdominant CTL clone against GP283−291 and clearance of ESC infection. Either WE or ESC infection activated CD8+ Tcells against the minor epi- tope, but in WE infection those minor-epitope T cells did not expand into a significant CTL response with lytic activity. It appears that, in WE infection, the fast development of CTLs against NP118−126 suppressed the viral load quickly enough that the weaker-stimulated CD8+ Tcells against GP283−291 did not have time to develop into a primary CTL re- sponse. These kinetic processes lead to indirect competition. Kinetic control suggests that immunodomination should be a quantitative phenomenon ordering epitopes into a hierarchy. An immunodomination hierarchy hasbeen demonstrated by Wettstein (1986). In addition, factors that alter the rate of CTL expansion against particular epitopes should be able to change the dominance hierarchy. Such changes in the hierarchy occur when the immune system has previously experienced an epitope. For example, if epitope A dominates epitope B in a naive host, then prior exposure only to B can reverse the dominance ranking and cause B to dominate A (Bennink and Doherty 1981; Jamieson and Ahmed 1989; Cole et al. This switch apparently occurs because secondary chal- lenge causes a more rapid CTL response, allowing CTLs against B to re- duce antigen load quickly enough to suppress a CTL response against A. CTL REPERTOIRE Why are CTL responses stronger against some epitopes than others? It could simply be that the immunodominant epitopes are expressed more commonly on cell surfaces than subdominant epitopes. However, Yewdell and Bennink (1999) summarize various lines of evidence argu- ing against a simple correlation between the abundance of presented epitopes and immunodominance, for example, the study by Weidt et al. Thus, immunodomination of CTL clones ap- pears to be influenced by biases in the CD8+ repertoire. Three important questions arise concerning CD8+ biases in the naive repertoire (Yewdell and Bennink 1999). First, does immunodomination IMMUNODOMINANCE WITHIN HOSTS 85 arise because more CD8+ cells respond to an immunodominant epi- tope or because CD8+ clones for immunodominant epitopes divide more quickly upon initial stimulation? The available data cannot distinguish between these alternatives. Second, how does variation between individuals in naive CD8+ reper- toires influence the hierarchical ordering of epitopes? Individual vari- ation can occur in self-peptides, TCR genes, and MHC genes. Negative selection shapes the TCR repertoire to avoid matching to self-peptides. TCR genes form the building blocks for combinatorial generation of TCR variability in each individual. Third, independently of self-peptides and TCR genes, do immuno- dominant epitopes stimulate TCRs more strongly? Favorable structural attributes of immunodominant epitopescould interact with relatively constant features of the TCR. Afew studies have compared immunodominance in humans with that in transgenic mice expressing thesamehuman MHC alleles. Both hu- mans and transgenic mice recognized the same immunodominant epi- topeswheninjected with viruses (Engelhard et al. Humans and mice that recognized the same peptide- MHC class I complex used TCRs composed of different Vα and Vβ germ- line components (Man et al. Thus, different self-peptides (mouse versus human) or variable TCR genes do not necessarily influence im- munodominance, although this is a rather weak conclusion. Instead, im- munodominance may depend on interactions between structural prop- erties of the epitopes and relatively constant features of TCRs (Yewdell and Bennink 1999). Negative selection against self-peptides can influence CD8+ response to particular epitopes. This was shown in a study of human infection by Epstein-Barr virus (Burrows et al. Individuals with the MHC class I allele B8 typically have immunodominant responses against EBNA3A325−333. T he CTLs in this immunodominant response have a high proportion of the same germlineTCR genes; that is, the response is composed of a very narrow set of CD8+ clones. CTL response against EBNA3A325−333 cross-reacts to the MHC class I allele HLA B*4402 when the host lacks this HLA allele. Individuals with both B8 and B*4402 produce a relatively weak CTL response against EBNA3A325−333. ThisweakerCTLresponse does not cross-react with 86 CHAPTER 6 B*4402 and has a TCR gene composition that differs from the TCRs in the strong CTL response of the B8-positive and B*4402-negative individuals. Self-reactivity apparently reduced the CTLs that cross-react with B*4402. Reduction of those dominant CTLs allows other CD8+ clones to expand, suggesting that the dominant CTLs in the B*4402-negative individuals suppress those CD8+ clones that expand in B 4402-positive individuals. An altered parasite peptide sometimes interferes with or enhances aCTLresponse against the original peptide, a phenomenon known as al- teredpeptide ligand (APL) (reviewed by Sette et al. Disruption of the lytic activity in an active CTL response provides one example of APL antagonism. In this case, the CTL response against the original epitope can be influenced by the presence of analtered epitope (peptide) with a small number of amino acid substitutions. The altered peptide prevents CTL lytic activity against cells expressing the original epitope.