By David N. Leff
Try this multiple-choice, not-so-trivial guessing game: How many organ transplants took place in the U.S. last year?
The correct answer is (b). Of those 17,840 transplants, kidneys accounted for a little more than half, with 8,944, followed by livers (4,091), pancreases (1,053), hearts (2,352) and lungs (1,470).
That's the good news. The bad news is that those 17,840 graft recipients, reprieved from early deaths by their own organs' failure, are paroled to life sentences of immunosuppression. It's no news that these powerful drugs - led nowadays by the likes of cyclosporin A - while preventing rejection of the intruding alien organ by the body's immune system, carry their own punitive side effects.
Transplant surgeon and immunologist Allan Kirk looked for a better way. He and a troop of rhesus monkeys found it, as Kirk reported in the June 1999 issue of Nature Medicine, under the title: "Treatment with humanized monoclonal antibody against CD154 prevents acute renal allograft rejection in nonhuman primates."
Kirk, an investigator at the Naval Medical Research Center in Bethesda, Md., is that article's lead author. Here is how he explained the seemingly incongruous preoccupation of the U.S. Navy with organ transplantation:
"The Navy has had a long interest in transplantation," he told BioWorld Today, "dating back over 20 years. The military applications are many, but most have been precluded by the toxic side effects of immunosuppression.
"Certainly," Kirk continued, "if you could freely transplant tissues from one individual to another, it would be very useful for catastrophic limb and tissue loss, organ failure, bone marrow replacement after ionizing radiation or chemical injury. But unfortunately the therapies that allow us to transplant are toxic enough in themselves that it needs extreme circumstances. Immunosuppression is just not applicable."
He added: "We're finding that a less toxic way of doing transplantation would be in the best interests not only of the civilian sector but also in the military." (See BioWorld Today, Feb. 12, 1999, p. 1.)
That alternative way hinged on a humanized monoclonal antibody called hu5C8, belonging to Biogen Inc., of Cambridge, Mass. It targets an immune-system antigen known variously as glycoprotein 39, CD40 ligand (CD40L) or CD154.
Costimulation Leads To Tolerance Of Donor Organs
Just how this costimulatory antigen-antibody duo sidetracks the immune system from attacking a mismatched donor organ remains unknown, Kirk allowed. "There are several places where it might be working," he pointed out. "CD40's ligand is expressed on activated T cells, so it could be doing something to either block the use by those cells of that ligand, or - by signaling through that CD40L - induce some sort of message that turns things off."
Another surmise invokes platelets. "Platelets also have CD40 ligand on them," Kirk observed, "and these are activated whenever you do surgery or trauma. Platelets probably have a lot to do with turning the immune system on in traumatic situations, such as organ transplant. So that hu5C8 monoclonal could be blocking the function of platelets as well.
"And certainly there may be other sites where CD40 ligand comes into play," he went on, "but the most important thing it does is bind to that CD40 antigen, which is on endothelial cells and antigen-presenting cells [APCs]. By inhibiting CD40 ligand's interaction with CD40, you inhibit APC and endothelial cells from being activated. And they're clearly important in initiating an immune response toward the graft."
To test this theory in mammalian practice, Kirk two years ago recruited the first of 18 rhesus monkeys at the Naval institute's primate facility. After transplanting them over time with mismatched donor kidneys, he administered Biogen's hu5C8 antibody to groups of recipient animals, with or without backup immunosuppressive agents.
As a baseline check, the first four recipient animals got donor kidneys only, with no further treatment. All four died of acute graft rejection within eight days.
Then, nine monkeys entered a six-month regimen of hu5C8 antibody therapy. On transplant surgery day, they received pre- and post-operative doses of the drug, followed by four weekly treatments, then once monthly for five months. Thereafter, the therapy stopped.
Record-Holding Simian Survivor 'Alive, Well'
"The longest survivor reported in our paper," Kirk noted, "was well over a year. One animal was a year off drug, so that would put him out at least a year and a half. Another monkey, not included in the paper's box score, Kirk added, "has been alive for over two years without any drugs at all. He's our record holder right now, still alive and well."
Five other monkeys received the six-month antibody dosage schedule, but in addition got conventional chronic immunosuppressive agents. Three of the five came down with graft rejection episodes, and one of them died. To account for this unexpected interference between the traditional and experimental treatments, Kirk observed, "The immune system doesn't do anything passively. It requires some sort of activity to mediate or to modulate its response. So if an immune cell sees an antigen, it has to make an active decision whether to attack or not attack, based on its active interaction with these molecules of context.
"And to do anything actively," he continued, "it has to work. If you put immune suppression on there, the immune system can't do anything, positive or negative. So it basically destroys the beauty of this type of therapy. It prevents the active immune regulation that forms a non-attacking, passive response."
That therapeutic response, mediating his monkeys' long-term survival, has Kirk "cautiously approaching human trials. I think we need to proceed cautiously," he said, "particularly given the fact that in order to test this hu5C8 drug on human graft recipients, the standard of care may need to be avoided. That is, if we can't use immunuosuppression because it counteracts the effect of the new drug, then we really have little safety net in moving forward. So the ethical design of those trials is not a trivial matter."
To cope with that potential roadblock, Kirk and his colleagues are "talking to very smart people, and rubbing our heads a lot." Still and all, he expects the first Phase I trial "within a year."