BETHESDA, Md. -- For the past three-quarters of a century,research in immunology has been based on the principle thatthe immune system discriminates between "self" and "non-self," according to Polly Matzinger, an immunologist at theNational Institute of Allergy and Infectious Disease. But inreality, she said, the immune system discriminates between thedangerous and the non-dangerous. Matzinger credits hercolleague, Ephraim Fuchs, with the basic concept. This theoryhas important implications for biotechnology.The old theory of self vs. foreign never gained the elegantsimplicity that theoreticians strive for in every scientific field."Definitions (of self) run the gamut, starting with everythingencoded by the genome," said Matzinger. "Some expand tocommensal organisms, too," and so self becomes "everythingunder the skin." Other definitions limit self to what iscommonly found in the major histocompatibility complex(MHC), or even some subset of the MHC. The list of suchdefinitions is long.

Matzinger proposed that instead of being activated by exposureto foreign materials, the immune system is turned on when itencounters tissue destruction. It goes into action when antigen-presenting cells (APCs) present large quantities of the resultingpeptides on their surfaces. When this happens, transmission ofso-called signal two activates immune cells. Only signal two canmuster an army against dangerous invaders, by activatingvirgin T cells and other virgin immune cells, which are thosecells that have not previously encountered antigen.

The only cells that can transmit signal two are those thatMatzinger calls "professional antigen-presenting cells," asopposed to ordinary APCs. The former have not beendefinitively identified, but "the interdigitating dendritic cells ...are my (and others') favorite candidates for true professionalAPCs," Matzinger wrote in an essay to be published in AnnualReviews of Immunology.

Signal one can activate experienced T cells, but its main job isto downregulate the immune system and keep it that way,which Matzinger thinks has to do with conservation ofresources. Signal one turns off resting T cells (except for killercells) and tells inactive cells to remain that way. It occurs whena T cell binds to an MHC molecule on a non-professional antigenpresenting cell.

This model allows for a much simpler explanation as to whythe immune system won't attack one's own healthy tissues.Instead of the universe of biochemistry of self, the systemmust only avoid attacking APCs. During development in thethymus, killer T cells that can recognize and attack APCs arekilled off by signal one, leaving only T cells that cannot attackAPCs.

"Since the virgin T cell population is tolerant of professionalAPC MHC antigen profile (which is each tissue's own set ofdiverse MHC/peptide complexes) and since other cell typescannot deliver signal two, the only antigens that shouldactivate virgin T cells are foreign antigens that have beencaptured by the professional APCs," according to Matzinger.

Matzinger's theory could help explain why the immune systemdoes not respond to tumors despite the fact that they haveelements of "non-self." Tumors are normal growing tissues and"until that tissue becomes necrotic, there is no reason for theimmune system to respond to it," she said.

Biotechnologists must "make that tumor look dangerous (to theimmune system)," said Matzinger. Glen Dranoff, a post-doctoralfellow in Richard Mulligan's laboratory at the MassachusettsInstitute of Technology, has had good results with granulocytecolony macrophage stimulating factor (GM-CSF) after trying aslew of lymphokines, said Matzinger.

Another application would be to tolerize patients to theproducts of gene therapy, said Matzinger. For example,inserting the gene that makes insulin into a diabetic couldcause an immune response. But putting insulin into non-APCtissue should result in immune tolerance, said Fuchs.

-- David Holzman Washington Editor

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