GAMMA/DELTA T CELL RECEPTORS KILL BLOOD-BORNETUMORS ONLY

By David N. LeffScience Editor

It would be a wonder if at least a few of the billions or trillions ofcells in a human body didn't turn malignant every day. That is whatactually happens, according to the theory of tumor surveillance.

A cancer arises from one hardy cell running amok and evading theimmune system's day-and-night patrol, which aims at mopping up allincipient tumors before they have a chance to get off the ground.

Since oncologists first posited the tumor surveillance concept in the1970s or earlier, it's been more an article of faith than a provenprocess. To quote a report in today's Nature: "The immunologicalmechanisms that control growth of preneoplastic cells are . . . notknown."

Now it looks as if certain T cell receptors called gamma/delta (gd)have at least a partial hand in scavenging would-be tumor cells beforethey get out of hand. That Nature article describes "Spontaneousresistance to acute T cell leukemias in TCRVg1.1Jg4Cg4 transgenicmice."

Its authors genetically engineered mice to produce these specific gd Tcell receptors. The transgenic animals, expressing these receptorgenes, slapped down not only two acute T cell leukemia cell lines butnearly all tumors generated from hematopoietic _ blood-forming _tissue.

Their prowess partly confirmed earlier research elsewhere thatfingered the gd T cell receptor as a likely player in the tumorsurveillance game. But this latest performance proved to be onlypartial. The same transgenic mice that conducted the search-and-destroy operation against hematopoietic cells took a dive whenconfronted with solid tumor cell lines, i.e., melanoma andfibrosarcomas.

Apparently, the body's tumor surveillance system relies on differentmechanisms to deal with blood-borne and solid-state malignancies.

Chromosome 6: Odds-On Favorite

Schizophrenia is not a disease; it's a complex of at least eight severepsychiatric disorders. Their adjectival names convey a sense of theschizophrenias' neurological heterogeneity and inexactness: Typical;Simple; Schizo-affective disorder; Schizophreniform disorder;Delusional disorder; Schizotypical personality disorder; Atypicalpsychosis; Mood incongruent psychotic affective illness.

One type or another of schizophrenia affects as many as one of every100 people in the population.

To get a handle on this blighter of lives and families, molecularbiologists are trying _ as they do for afflictions in general _ tolocate the mutant gene or genes on the human genome that make theschizophrenias happen. Their quest turns into a numbers game,weighing statistical odds and probabilities of linking allelic genevariants to affected individuals and their families.

Applying such linkage analysis, Scott Diehl, in the molecularepidemiology and disease indicators branch of the National Instituteof Dental Research, proposes a place to look for the DNA sequenceof schizophrenia. He is senior author of a paper in this month'sNature Genetics titled "Evidence for a susceptibility locus forschizophrenia on chromosome 6pter-p22." That is a region on sixbeginning at the tip of its short arm.

To find this spot on the chromosomal map, Diehl and his co-authorsanalyzed the DNA of 992 individuals belonging to 186 families withtwo or more schizophrenic members. It takes such large pedigreenumbers to perform statistically valid linkage analysis ofpolymorphic DNA markers in such a multiform disorder.

Those 186 multiplex families, of the same geographic racial andethnic origin, were collected in Ireland between 1988 and 1992. Theyrepresent a natural resource for researchers in this field.

In reaching their conclusion pointing to the location of theschizophrenia locus, the team reported a "lod score" of 3.9. A lodscore of 3.0, Diehl said, "is the traditional threshold for significantmapping results."

He observed that barring the low risk of pure chance, the evidence _"supportive but not conclusive" _ suggests that his team hasidentified either a major gene playing a role in a subset of families, ora lesser gene implicated in a majority of schizophrenia cases. Eitherway, he concluded, "other researchers will have to confirm thesefindings in different groups of families." n

(c) 1997 American Health Consultants. All rights reserved.