Editor's note: Science Scan is a roundup of recently published biotechnology-relevant research.

Identical twins enjoy a free pass when it comes to organ transplantation. Because their immune systems are neatly matched, if one monozygotic sibling comes down with, say, leukemia, the other twin can donate replacement bone marrow without fear of graft rejection.

Polyzygotic brothers and sisters offer each other less complete protection, because their immune defenses are armed with only partially compatible cells. And if a child diagnosed with leukemia has to go into the open donor market for an allogeneic - nonsimilar - gift of bone marrow, the odds of that patient's survival are sobering. That unrelated gift graft can turn savagely against its recipient's gut, skin and liver epithelia, to inflict lethal graft-vs.-host disease (GVHD).

"The occurrence of significant GVHD in a patient who gets a transplant from a brother or sister," observed hematologist/oncologist James Ferrara, "is probably about 30 percent. For unrelated volunteer donors," he added, "the incidence is perhaps 60 percent. Some 5,000 allogeneic [nongenetic identical] bone-marrow transplants are performed each year in the U.S. We estimate 15 percent of those patients will die of GVHD or its complications.

"The primary complication when they die is infection," Ferrara pointed out, "because they are immunosuppressed to start with, and then we further immunosuppress them with additional agents. So if someone dies with an infection while being actively treated for GVHD, the underlying cause of death is GVHD. At least 500 patients a year die of this disease, and that number may be up to 1,000."

Ferrara directs the programs of adult and pediatric bone marrow transplantation at the University of Michigan Cancer Center in Ann Arbor. He is senior author of a paper in the June 2002 issue of Nature Medicine titled: "Acute graft-versus-host disease does not require alloantigen expression on host epithelium."

"Our finding demonstrates," Ferrara told BioWorld Today, "that the mechanism of the damage caused in this process of acute graft-vs.-host disease is not what was initially thought. It was thought that cytolytic [cell-killing] T lymphocytes from the donor graft directly attack the host patient's skin, gut and liver. We showed that that attack is not direct but indirect, and that those T cells are activated in host tissues by specialized antigen-presenting cells. But that damage is largely mediated not by T cells, but by inflammatory cytokines - notably tumor necrosis factor-alpha [TNF-alpha] and interleukin-1 [IL-1], released by those T cells. But it does not require direct contact between the T cells and the target tissues.

"People have assumed it was the T cells inflicting the damage directly," Ferrara noted. "But in fact, they become activated and secrete cytokines, which can travel through the bloodstream. So it's the difference between a direct attack by ground troops and a remote general air strike.

"Our paper shows that cytokines are the primary clinical players here," he pointed out. "That helps us look at new ways to both prevent and treat GVHD. We are now focusing those ways on either reducing or eliminating the antigen-presenting cell."

Ferrara summed up the novel drug-therapy strategies now beginning clinical trials.

"One would be - for blocking the cytokines - the use of an engineered, soluble TNF receptor called etanercept [Immunex's Enbrel] that can block TNF. Another, infliximab [Centocor's Remicade], is a monoclonal antibody against TNF. These are just now entering clinical trials. The other approach is to reduce or eliminate host antigen-presenting cells [APCs]. One way is to use an antibody called Campath [from Ilex Oncology]. It recognizes a cell-surface antigen on all white cells, including APCs, which Campath could eliminate.

Ferrara concluded: "GVHD is a complication of all bone-marrow transplants - the differences between donor and recipient - that keeps us from being able to offer transplants tomorrow, including some solid-organ grafts, to patients who need them. But at the moment, you have to have a perfect match, even from an unrelated donor."

Knockout Mouse Model Cracks Conundrum Of Fragile X Retardation, Hints At Eventual Therapy

Fragile X syndrome is the commonest inherited form of mental retardation. It afflicts 1 in 4,000 boys and 1 in 8,000 girls, with no cure or effective therapy. The syndrome is due to a mutation in the Fmr1 gene, which causes loss of the FMRP protein. Clarifying how this loss can lead to mental retardation is proposed by neuroscientists at Brown University in Providence, R.I. Their report, in the Proceedings of the National Academy of Sciences (PNAS) dated May 28, 2002, is titled: "Altered synaptic plasticity in a mouse model of fragile X mental retardation." Their finding "suggests new therapeutic approaches for fragile X syndrome."

The authors found that genetically engineered mice lacking FMRP showed enhanced long-term depression, which could prevent strong connections between neurons in their hippocampus - thus hampering learning and memory.

Transplantation of Human Tissues Into Brains Of Parkinson's Patients Leaves Some Side Effects

Experimental transplantation of dopamine-secreting human embryonic tissue into the brains of patients with Parkinson's disease (PD) continues to attract attention. Fourteen such recipients were studied 11 years after their transplants, as reported in Nature Neuroscience published online June 3, 2002. The paper's title: "Dyskinesias following neural transplantation in Parkinson's disease."

It found that dynkinesias (abnormal involuntary movements) increased during postoperative time-out phases. The article's authors, neuroscientists at the University of Lund in Sweden, report that symptom relief is not correlated with the severity of these movement disorders after the transplants - which disabled one of the 14 probands. They suggest that it may be possible to prevent the development of these adverse consequences, and conclude that their findings provide no evidence for stopping further efforts to develop cell transplantation therapy for PD.