Secret to tamping down GVHD may lie in microbial genetics – Fred Hutchinson Cancer Center

T cells: BMTs double-edged sword

Bone marrow transplants, also known as blood stem cell transplants or hematopoietic stem cell transplants (HST), revolutionized blood cancer treatment. After a conditioning regimen wipes out as many blood cancer cells as possible and also wiping out healthy blood stem cells transplant recipients receive healthy new donor bone marrow or blood stem cells. These take root in the bone marrow and grow new oxygen-carrying red blood cells and infection-fighting white blood cells.

With the stem cells come mature donor immune cells, including T cells,a specialized type of immune cell critical both to a bone marrow transplants success in treating cancer, and the driving force behind GVHD.

T cells use a specialized molecule, called a T-cell receptor, or TCR, to read bits of proteins pinned to the surface of cells by a molecular peg. These protein-peg complexes act as bulletins of a cells health status, and T cells are trained to leave healthy cells alone.

But when a T cell is dumped in a new environment, they can misread these bulletins. These T cells may attack a BMT recipients healthy tissue, even as some donor T cells kill off lingering tumor cells and prevent relapse.

To help ensure that donor T cells understand the messages theyre reading, hematologists try to ensure that the pegs theyll see in a recipient match the pegs theyre used to seeing in their home turf, the donor. If they are well-matched, T cells are more likely to understand the message that their new host is self and safe.

This is called tissue typing.

But tissue typing isnt perfect. The pegs, called HLA, for human leukocyte antigen (or MHC, for major histocompatibility complex) are among the most variable genes humans have. And each person has several MHC genes, each with its own dizzying variety. On top of this, the little protein messages cradled by MHC molecules can vary between recipient and donor just enough to send a "danger!" signal to donor T cells (even when MHC genes match perfectly).

Right now, treatments for GVHD, like corticosteroids, muffle the anti-tumor cells along with those driving GVHD.

Its the holy grail of transplant: separating GVHD from the graft-vs.-leukemia effect, Yeh said. I wanted to understand how to improve GVHD from the standpoint of the individual T cells.

He hoped that if he could identify the GVHD-promoting T cells, he would be able to devise strategies to remove them, leaving only the leukemia-targeting cells behind.

Still working from the assumption that recipient and donor genetics would be the key to solving this dilemma, Yeh performed twin transplant studies. In these, bone marrow from one donor mouse is split apart and transplanted into two genetically identical recipient mice.

Yeh and Hill expected that, faced with the same genetic milieu, the same T cells that respond to the new environment would expand in each recipient. (TCRs are even more variable than MHCs: each new T cell builds a bespoke TCR that is one of more than a quadrillion possible TCRs.)

By comparing the donor TCRs in each recipient, the scientists expected it would be possible to find the recipient-targeting TCRs that could drive GVHD.

But the T cells confounded them. In each recipient, a pool of T cells with certain TCRs would expand, suggesting that they were responding to something in their new environment.

Even in completely identical donor and recipients, theres almost no overlap in which T cells expanded, Hill said. This is shocking given how we currently think about alloreactivity [the T-cell response to MHC variants].

But an individual may have billions of different TCRs floating around some found on only a single T cell. Yeh, working with Fred Hutch computational biologist Phil Bradley, PhD, developed mathematical models to confirm that the lack of overlap didnt reflect the chance that each twin had received a different set of rare TCRs.

Yeh found that antibiotic treatment (two weeks prior to one week after transplant), but not total-body irradiation, reduced the pool of T cells that expanded after transplant. Previous work had suggested that the microbiome can influence GVHD through general immune mechanisms. What if the T cells were responding to the microbes through their TCRs?

Yeh took advantage of the fact that mice bred in different facilities have different microbiome makeups. He gave a bone marrow transplant to two sets of recipient mice (with higher and lower levels of a certain bacterium). To the donor bone marrow, he added T cells genetically engineered to carry TCRs that detect the bacterium.

He found that not only did the bacterium-targeting T cells expand more in the mice with higher levels of the bacterium, but also exacerbated GVHD lethality. Yeh further showed that GVHD does not originate with the bacterium-targeting T cells.

By themselves they dont do too much, he said.

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Secret to tamping down GVHD may lie in microbial genetics - Fred Hutchinson Cancer Center