October 17, 2007

Taming intolerance in bone marrowtransplantation
RIKEN researchers unveil a novel advance in drug-free, cell-based immunotherapy for
combating complications of bone marrow transplantation.
Scientists from the RIKEN Research Center for Allergy and Immunology, Yokohama, led
by Katsuaki Satoh, and from the University of Tokyo have improved a new therapy
directed against a common cause of disease and death arising from bone marrowtransplantation (BMT) in mice. The researchers report in the latest issue of the journal
Blood, that their non-pharmacological approach, using specially manipulated immune
cells, suppresses a common and deadly complication - graft-versus-host disease(GVHD) - of BMT.
BMT has now become a common therapy for various types of cancers, immune
deficiency disorders and genetic diseases. In allogeneic BMT (alloBMT), unhealthy or
damaged bone marrow cells are replaced with healthy tissue from agenetically-matched donor. Genetic matching involves an array of specific proteins antigens - on the surface of white blood cells called leukocytes. The genetic identity of
an individual's immune system is determined largely by this human leukocyte antigen(HLA) array. A transplantation is more likely to be successful when a subset of all theHLA proteins - the major HLA antigens - is carefully matched between donor andrecipient.
Host rejection of donor tissues is not the only major concern in transplantation medicine;
alloBMT is often accompanied by GVHD. This disease amounts to a form of donor
tissue intolerance - ranging from mild to deadly - whereby specific donor immune cells,T-cells, do not recognize the HLA identity of recipient cells and so attack host tissues.
Current methods to reduce GVHD involve using immunosuppressive drugs and/orremoving as many of the specific donor T-cells as possible prior to transplantation.
These treatments have their own problems, however, since along with the reduced
incidence of GVHD there are often increases in transplant rejection rates, severe
immunosuppression, lethal infections and other serious side-effects.

The researchers worked beyond these therapies within the still largely experimental
field of 'cell-based tolerogenic immunotherapy,' which, as the term 'tolerogenic' implies,
involves 'pacifying' pivotal warring players of the recipient and donor immune systems.
The group focused specifically on the key modulators and stimulators of cell-mediatedimmune responses, dendritic cells (DCs). Before T-cells can be activated to drive GVHD,
they must first sample the HLA antigens, in a DC-mediated antigen presenting process.
T-cell activation is extremely complicated and can only occur when the antigen
presenting process works in concert with proper co-stimulatory signals. The RIKEN
researchers exploited this inherent complexity to suppress GVHD.
The team subjected isolated mouse recipient DCs to a regimen of immunosuppressive
chemicals to yield 'tolerogenic DCs' with a compromised capacity for T-cell stimulation.
Because these modified DCs demonstrate a greater capacity for modulating
T-cell-mediated immune responses in recipient mice than do other tolerogenic DCs, theresearchers describe these cells as 'regulatory DCs,' with the designation DCreg. These
researchers had previously shown that DCreg protect mice from an acute form of GVHD
with an early onset after alloBMT.
The current study demonstrates that DCreg also protect alloBMT-treated mice from aless understood and more intractable form of late onset GVHD - chronic GVHD - byspecifically modulating, and essentially calming, the T-cell response of transplanted
tissues. Importantly, some recipient DCreg which were first exposed to fragments ofvarious donor proteins before being reintroduced to the alloBMT-treated recipient mice,
reduced the anti-host reactivity of the donor T-cells in an antigen-specific way. Crucially,
human DCreg also demonstrate similar T-cell pacifying profiles. These findings are all themore exciting since the mice used here share critical physical and functional featureswith human chronic GVHD.
This approach is also attractive because it may spare patients from a life-long regimenof debilitating immunosuppressive drugs. Since small animal studies are not always
easily extrapolated to clinical settings, the RIKEN team will next strive to demonstratethat this approach can be used to promote transplant tolerance in humans.
Original work:
Fujita, S., Sato, Y., Sato, k., Eizumi, K., Fukaya, T., Kubo, M., Yamashita, N., Sato, K.
Regulatory dendritic cells protect against cutaneous chronic graft-versus-host diseasemediated through CD4+CD25+Foxp3+ regulatory T cells. Blood, online Aug. 8, 2007.

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