By David N. Leff
One collateral reason the British army lost the American Revolutionary War is the color of their uniforms. When the minutemen, firing from behind trees and stone walls, aimed their squirrel rifles at the enemy, they faced a highly visible target. King George¿s soldiers weren¿t called redcoats for nothing.
Nowadays, most armies dress their troops ¿ clear up to desk-bound generals ¿ in camouflage uniforms patterned to blend invisibly into the desert or jungle environment in which they expect to fight. Picture an enemy force out there, in camouflaged uniforms marked by some kind of printed or patched-on optical recognition code.
The soldiers out in the battlefield can¿t identify their foe, because they don¿t have the decoding device. But there¿s a specially equipped reconnaissance unit attached to your forces. They¿re the only ones that can really spot the enemy when it infiltrates, and mobilize your troops to counterattack.
That pretty much describes the seesawing strategies pursued by the body¿s immune defenses, and by its hostile viral enemies. In this case, the pathogen¿s camouflage code consists of antigenic proteins, which cells of the immune system ¿ mainly T lymphocytes ¿ are programmed to grab onto and eliminate.
But you can¿t grab what you can¿t see. Before a T cell can seize and destroy its antigenic enemy, an elite contingent of the immune system, the Major Histocompatibility Complex Class I (MHC I), must bring that antigen to the notice of the killer T cell ¿ i.e., its cytotoxic lymphocyte (CTL).
According to the conventional immunological paradigm, explained immunologist Kenneth Rock, ¿the Class I antigen presentation pathway was known to allow the immune surveillance system to check the health of individual cells throughout the body, by continually monitoring what molecules those cells themselves were producing. This pathway was exclusively concerned with monitoring cells¿ expressed genes. If you had exogenous antigenic proteins in the space outside of the endogenous cell, those cells were unable to take them up and present them on Class I.¿
Rock is chairman of pathology at the University of Massachusetts Medical Center, in Worcester. He and his group discovered in 1990 that there were some specialized antigen-presenting cells to which those rules didn¿t apply. They turned out to be dendritic cells, produced by the bone marrow, and capable of picking up proteins or foreign antigens from the fluids outside the cell and displaying those on MHC I, for the attention of the T cells.
Those cellular couriers that freight these antigenic particles to the T lymphocytes, the dendritic cells, are better known as garbage collectors, ingesting useless molecular detritus and spitting out its broken-down particulate debris.
But Rock saw dendritic cells as having a loftier mission. After digesting their ingested waste matter into tiny ¿ but still highly antigenic ¿ particles, they lay these on the doorstep of the MHC I molecules, which hand them over to the CTL hit-cells for termination. That¿s why they join the ranks of MHC¿s ¿professional antigen-presenting cells.¿
Rock is senior author of a paper in the current issue of Nature, dated March 4, 1999, and titled ¿Cytotoxic T-cell immunity to virus-infected non-haematopoietic cells requires presentation of exogenous antigen.¿ It makes the point, he told BioWorld Today, that this new exogenous pathway ¿is the only pathway, based on our data, by which the immune system can detect a viral infection ¿ some pathological process that¿s occurring out in the peripheral tissue.¿
Implications For Novel Vaccines Against Viral Evasion
His exogenous immune pathway, Rock suggested, ¿has implications, I think, for things like vaccine development and delivery. A number of groups are attempting to develop genetic vaccines, which would in effect mean transfecting cells of target tissues with genes. They hope to get these to stimulate the immune system, make it more immunogenic.¿
His Nature article describes how Rock experimentally confirmed in vivo his 1990 in vitro evidence of the exogenous immune pathway:
¿First, we developed a viral system where we could be absolutely certain what cells in living mice it would infect,¿ he said. ¿For this, the paper¿s lead author, postdoctorate Luis Sigal, chose the poliovirus [PV] because it¿s incapable of infecting mouse cells, because they lack the PV receptor. Using that virus, we could control what cells it infected in mice by inserting a transgene that expresses the PV receptor.
¿So, we took such transgenic animals,¿ Rock went on, ¿and created an experimental situation where all of their cells, except those of hematopoietic origin, could potentially be infected with the virus. We excluded the hematopoietic system, because it produces the dendritic cell itself, which would deliver the antigen for display via the conventional endogenous Class I pathway. We did this by eliminating the transgenic animal¿s own blood-forming system. Then, by a bone-marrow transplant, we gave it cells that lacked that PV receptor.
Mice Performed On Cue, Eliciting CTLs
¿We created an experimental situation where the bodily tissues could get infected ¿ but none of the professional antigen-presenting cells that would come from the bone marrow. And then we could study how that animal was capable or not of recognizing the poliovirus infection.
¿One of the major immune responses to viruses,¿ Rock pointed out, ¿is the generation of killer cells ¿ CTLs ¿ that will recognize virally infected cells and eliminate them. So we asked whether the animals could generate such a response. If those dendritic cells couldn¿t present antigen, the mouse would get absolutely no CTL protection. So, this would be an obligatory mechanism for generating such immunity with tissue-targeting virus.
¿We found that the mice were perfectly capable of mounting an immune response to PV, but only if the bone marrow that we gave them was capable of presenting exogenous, that is, extracellular, antigens,¿ he said. ¿So, what this indicated is that although the tissues in this animal were producing lots of PV antigens, their immune system couldn¿t see it unless the bone marrow cells could acquire it and display it.¿
Rock has a pending patent protecting ¿the underlying antigen-presenting pathway, specifically in using particulate kinds of antigen to elicit CTL responses with protein antigens.¿ It is licensed to Seattle-based Corixa Corp., of which he is a co-founder and scientific advisor. The company, Rock concluded, ¿is very actively pursuing that technology for cancer-vaccine delivery systems, and also for infectious diseases.¿ n