Dr. Elaine Sloand and her colleagues at the National Institutes of Health have just published an article in Blood that adds some pieces to the puzzle of why some folks with MDS respond to immunosuppressive therapy [IST] -- that its, ATG & cyclosporine or Campath.
The article is highly technical and well above my pay grade, but its conclusions are pretty interesting and, I think, worth sharing here. (If you want to puzzle it out for yourself, you can find the abstract
here, or
email me if you'd like a PDF of the full report.)
Dr. Sloand examined MDSers who have the Trisomy 8 chromosomal abnormality and found that they were much more likely than regular folks and somewhat more likely than other MDSers to have a version of the WT1 gene in their Trisomy 8 stem cells. Previous NIH studies have shown that folks with Trisomy 8 are more likely to respond to IST, which is why Dr. Sloand has been focusing on this subset of MDSers.
Dr. Sloand found that these same Trisomy 8 folks have CD4 and CD8 T cell lymphocytes that are programmed to attack the WT1 gene. So WT1 appears to be the spark that sets off the war between T cells and marrow stem cells that I described in an earlier post.
When the researchers added some of those WT1-sensitive CD8 T cells to some perfectly normal bone marrow stem cells, blood production was suppressed. That suggests that T cells wired this particular way can suppress blood production by normal stem cells -- in other words, the T cells aren't just messing with the Trisomy 8 stem cells, they are messing up blood production more generally.
Connecting the dots, folks with Trisomy 8 MDS have a T cell war going on in their bone marrow, in which WT1-sensitive T cells attack Trisomy 8 stem cells carrying the the WT1 gene, and create collateral damage among all the innocent normal stem cells, suppressing overall blood production.
When Dr. Sloand compared the marrow of folks before and after IST, she found that the number of Trisomy 8 stem cells can actually increase after a positive response to immunosuppression -- yet the marrow otherwise returns to normal and blood production improves. That suggests the dysplasia in this kind of myelodysplasia is more the result of the immune attack than poor blood production by the Trisomy 8 stem cells.
It also suggests that immunosuppression can allow the MDS clone to continue to grow unchecked. But Dr. Sloand and her colleagues write that, in a decade of experience using immunosuppression to treat MDS, they have not found any increased conversion to leukemia among folks treated with this therapy.