Psoriasis, unlike some other autoimmune diseases, such as multiplesclerosis or systemic lupus erythematosus, is not life-threatening. Butit can be life-blighting.An estimated 2 percent of the U.S. population suffers from psoriasisvulgaris, said cell biologist David Wilkinson, a senior scientist at thePsoriasis Research Institute in Palo Alto, Calif. That incidence worksout at some five million men and women, afflicted with the unsightly,irritating patches of raised, discolored skin, covered with silvery-white scales that shed. These plaques typically occur on elbows,knees or scalp, but can disfigure trunk, chest, buttocks or other areasof the body. Often, small separate psoriatic lesions coalesce to formlarge and spreading masses.Besides the physical discomfort psoriasis inflicts, it frequently causeslifelong psychiatric dysfunction, in sufferers who quail from showingthemselves, and their stigmata, in public.A psoriasis sufferer can blame his or her own immune defenses forbringing on the disease. Like a traitorous soldier who deserts to theenemy, a set of white blood cells called T cells, which are supposed todeploy their receptors to counterattack an invading force of viruses,bacteria or whatever, instead treacherously release mediators thatindirectly waylay keratinocytes -- skin cells in the epidermis. Thisautoimmune assault causes the inflamed keratinocytes to starthyperproliferating out of control.Those self-destructive T cell receptors, and the antigens they target,are both on the "most wanted" list of psoriasis researcherseverywhere, but so far have evaded capture, or even identification.Clinical Trials: This Quarter Or Next"Our approach," Said Immunologist Jennie Chang, a senior scientificinvestigator at Immune Response Corp., "is to try to identify theputative pathogenic T cells, and their receptors, which are seeing theantigen in the skin. Then we can use part of that receptor in avaccine, to generate a therapeutic response against those T cells."She compares this strategy to making an antiviral vaccine, aimed atthe virus's surface protein.Immune Response, of Carlsbad, Calif., is hot on the trail of these tell-tale T cell receptors, and shooting to have a therapeutic (not apreventive) vaccine ready for clinical trial by early next year.That is the hope expressed by Chang, the first author of a paper inTuesday's Proceedings of the National Academy of Sciences (PNAS),titled: "CD8+ T cells in psoriatic lesions preferentially use T cellreceptor Vb3 and/or Vb13.1 genes."Chang told BioWorld Today, "Since we believe that the 3 and 13.1cells are the bad guys. we want to get rid of them, right? Ourapproach is to use a part of those T cell receptors that recognizethose bad pathogens as a vaccine to immunize a patient. That way wehope to generate an anti-autoimmune response against those cellsthat bear the 13.1 and 3 T cell receptor gene segments."Before this can happen, Chang needs to verify her PNAS findings inanother half-dozen patients. "We are trying to accumulate 15 patientsas a base for a Phase I/II clinical trial."Her psoriatic-plaque skin samples come from Wilkinson of the PaloAlto Institute, an independent, privately funded institution. A co-author of the PNAS paper, Wilkinson told BioWorld Today, "Werecruited the patients and supplied the biopsies to Immune Responseunder contract."At the Institute's clinical center, he and his associates shaved smallsections of epidermis and underlying papillary dermis, threecentimeters square by just under half a centimeter thick, frompsoriatic lesions on the back, arm, leg, thigh or abdomen ofvolunteering patients. The analysis of these samples by Chang andher colleagues at Immune Response led to their T cell receptorfindings reported in the current PNAS.`Turning' A Hostile Immune SystemT cells are designed to snare antigens, much along the lines ofantibodies generated by the immune system's B cells. The genes thatencode receptors to a T cell chain's variable region (which locksonto a specific antigen), Chang explained, consist of severalscrambled segments, arranged along the V (for "variable") beta chainof the receptor molecule.By subjecting those psoriatic plaque biopsies to genetic analysis, theydiscovered that in such patients, the rogue autoimmune receptors areencoded preferentially (compared to non-psoriatic cells) by genesegments Vb3 and/or Vb13.1. That bias was the clue they needed toconstruct T cell receptors against those pathogenic targets, for use ina clinical trial of the resulting therapeutic vaccine. Its purpose, Changexplained, is to stimulate the immune system to attack the offendingT cells, rather than taking them on directly.One residual uncertainty nagged them: What if those pathogenic genesegments were specific, not to psoriasis, but to any skininflammation?A local dermatology clinic supplied Chang with samples from theitchy patches of three people with a different common skin disorder,atopic dermatitis. No problem: "No evidence of elevated Vb3 orVb13.1 expression in the skin was found in these patients," PNASreported.When clinical trial time comes, the Palo Alto Institute's clinicalcenter expects to manage the study, Wilkinson said, finding andevaluating patients, and administering the putative vaccine.Chang emphasizes another fact: "In AIDS patients, psoriasisworsens. "They are probably already predisposed genetically topsoriasis, she observed, "and find that it sets in after they becomeinfected with HIV."The point she makes is that "In AIDS patients, CD4+ T cells are theones that get wiped out, not CD8. So our data would indicate that Vb-bearing CD8+ cells are more important in psoriasis. Otherwise, if theskin disease were mediated by CD4s, then in HIV-infected persons,the psoriasis should get better, not worse."
-- David N. Leff Science Editor
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