MASS GENERAL, BIOTRANSPLANT REPORT TAMINGDONOR ANTIGENS WITHOUT WHOLE-BODY IRRADIATION
By David N. LeffScience Editor
When a transplant surgeon grafts a donor organ into a patient, he triesto teach the recipient's immune system a lesson it will never forget.
Actually, what that physician wants to do is make his patient's T cellsforget the lessons they learned in earliest infancy _ namely, how totell friend from foe. T cells lead the immune attack that brings ongraft rejection.
As an immune system matures, the thymus gland instructs it how torecognize "self" _ that is, the body's own cells and molecules _from alien "non-self" antigens. This obligatory course in "ImmuneSelf-Defense 101" lasts most people a lifetime. It's when a systemforgets this precious skill, and starts to see self antigens as foreigners,that autoimmune diseases happen.
But when another person's donor heart or kidney, or other organ, issuddenly stitched into a body, the immune system goes on red alert toreject the intruder.
Graft rejection is a recipient's prime peril, and his physician's worstbugaboo. To prevent or reverse this organ destruction, transplantimmunologists rely on two main strategies:
* One is to weaken the recipient's immune system to a point whereit's too feeble to overthrow the alien organ, but still has enoughoomph to fight off major infections. So they dose their patients withpowerful immunosuppressants, such as cyclosporin A, azothiaprinand imuran.
* Their other ploy is to send the thymus gland to reform school, andeducate its T lymphocytes to accept the donor cells as "self." Thisconditioning regimen involves exposing the patient's bone marrow towhole-body irradiation, which rubs out many of the stem cells thatdevelop into T cells, and create "space" in which donor cells canengraft. Then, they add treatment with antibodies against major T-cell receptors, and finally inject donor cells into this boot camp forlearning immune tolerance.
World Conclave Hears How To Skip Irradiation
Last week in Barcelona, Spain, the XVI International Conference ofthe Transplantation Society heard of a "first demonstration" of a newapproach that works without recourse to irradiation orimmunosuppressive drugs. Immunologist Megan Sykes reported to asession on "Chimerism and Tolerance" her group's "achievement ofhigh levels of mixed allogeneic chimerism without whole bodyirradiation or myelosuppressive drugs."
Sykes is at the Transplantation Biology Research Center ofMassachusetts General Hospital (MGH) in Boston. The center'sdirector is David Sachs, who chairs the scientific advisory board ofBioTransplant Inc. in Charlestown, Mass. BioTransplant sponsoredthe work reported by five oral presentations and a score of posters atthe Barcelona conclave.
The company's chief scientific officer and senior vice president ofresearch is immunologist Julia Greenstein. "What Megan Sykesshowed," she told BioWorld Today, "is that we can totally eliminatethe need for whole-body irradiation by enhancing the number ofdonor bone marrow cells transplanted. These," she added,"incorporate stem cells intended to indoctrinate the recipient's Tcells."
In mice, Sykes and her co-authors created "space" in the thymus _vocational school for T cells _ and injected into their bloodstream20 times the usual dose of donor bone marrow cells, deliberatelymismatched. They thus got the message, and learned to tolerate donorskin grafts permanently.
"And so," Greenstein observed, "the conditioning regimen that onewould have to envision clinically is significantly simplified by thepotential application of this rodent study to primates and then toman."
BioTransplant now has both such studies under way. "In cynomolgusmonkeys," Greenstein said, "in allotransplantation [same-speciesdonor] we've shown the ability to induce this chimerism andtolerance. Those animals received life-supporting allogeneic kidneygrafts and have existed for two years post-transplant, having beenirradiated without any chronic immunosuppression in those totallyforeign kidneys."
Whereupon, in June of this year, MGH started a physician-sponsoredclinical trial of the innovation in kidney transplant patients.
Monoclonal Scores In Recipient Monkeys, Humans
In Barcelona, the session on "Immunosuppression and Anti-T-CellAgents" heard the outcome of a quite different human trial.Transplant surgeon Jean-Paul Squifflet at Belgium's University ofLouvain reported on a randomized study of a novel monoclonalantibody, "BTI-322 for induction therapy after renal transplantation."
BTI-322 targets important receptors on the surface of T cells and NK(natural killer) cells. Two immunologists at Louvain, Herv Bazinand Dominique Latinne, developed it in recent years, and theuniversity licensed it to BioTransplant.
In Squifflet's Phase I/II trial, 12 of 20 (60 percent) cadaver kidneyrecipients who received conventional triple-drug immunosuppressionsuffered acute rejection of their graft. But in 18 others who got BTI-322 as well as the standard drug therapy, only four (22 percent)suffered acute rejection during the six-month observation period.
In a second Phase I/II study at Louvain, reported to the conference byLatinne, 10 of 11 patients experiencing a rejection event responded toBTI-322 treatment.
Greenstein presented a poster in Barcelona reporting that "Anti-CD2monoclonal antibody elicits alloantigen hyporesponsiveness[tolerance] in vitro and in vivo." She observed that "the monoclonalwould be used in what we call both alloimmune and xenoimmune[transplants across discordant species lines] to eliminate peripheralmaturity T cells.
"In order to start T-cell education," Greenstein explained, "you haveto get rid of all the T cells that are already created in an individual." n
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