Temporary removal of CD4+ T cells after an allogeneic hematopoietic stem-cell transplant leads to changes in the nature of CD8+ T cells that, according to a mouse study, help prevent graft-versus-host disease without jeopardizing the therapy's potential to eliminate leukemia or lymphoma.

The removal of CD4+ T cells for a month or two soon after an allogeneic hematopoietic stem cell transplant (HSCT) could prevent complications of graft-versus-host disease (GVHD) without jeopardizing the therapy's potential to cure patients with leukemia or lymphoma.

According to a new study in mice, temporary depletion of CD4+ T cells produces an increase in interferon-γ and a decrease in IL2. These cytokine changes result in high expression levels of PD-L1 in the gut, liver, and lung, which are normally susceptible to attack from donor immune cells. However, when PD-L1 in these tissues binds the PD-1 receptor on the surface of infiltrating cytotoxic CD8+ T cells, the alloreactive immune response is tamped down, avoiding GVHD.

Led by Defu Zeng, MD, an immunologist at the Beckman Research Institute of City of Hope in Duarte, CA, the study authors also report that the absence of CD4+ T cells—and the jolt of interferon-γ this spurs—has a more direct effect on CD8+ T cells themselves.

In CD8+ T cells that home to the gut, liver, and lung, PD-1 receptor levels go up, increasing PD-L1 binding—and thus tolerance—in these GVHD-prone tissues. Meanwhile, in CD8+ T cells that enter lymphoid tissues (spleen, bone marrow, and lymph nodes), expression of PD-L1 and its alternative receptor, CD80, both become elevated. Because CD80 and PD-L1 have immunostimulatory effects when they bind, CD8+ T cells in the lymphatic system interact and expand their numbers locally to fight off malignancy. The net effect: strong graft-versus-tumor effects in lymphoid tissues, but no GVHD elsewhere in the body.

“The clinical relevance [of this study] is undeniable,” says Xian Li, MD, PhD, a transplant immunologist from Houston Methodist Hospital in Texas, who was not involved in the research. The trouble, he notes, will be putting the findings into practice. “The challenges in moving forward are to target the right cells in the right place at the right time, which is difficult in humans.”

That's what Paul Martin, MD, a hematologist at the Fred Hutchinson Cancer Research Center in Seattle, WA, learned when he led a trial in the mid-1990s that involved depleting donor CD4+ T cells ex vivo prior to HSCT. The approach did not reduce rates of GVHD.

Martin, co-author of the current study, now suspects that some small number of CD4+ T cells made it into the engrafted bone marrow and expanded post-transplant—or that new donor CD4+ T cells were generated in the thymus. Either way, he says, the problem is the same: The earlier protocol didn't include removing CD4+ T cells in the immediate post-transplant period, which he, Zeng, and their colleagues have now shown is needed to keep PD-L1 levels up—and consequently CD8+ T-cell numbers down—in tissues susceptible to GVHD. “In vivo CD4 depletion might be needed to remove the first waves of donor-derived CD4+ T cells,” Martin says.

Looking ahead, Zeng, Martin, and City of Hope's Ryotaro Nakamura, MD, are planning a clinical trial to test that approach. They have partnered with Tokyo-based IDAC Theranostics, which will soon run a first-in-human trial in Japan involving an anti-CD4 drug (IT1208) in patients with solid tumors. Assuming the drug is safe, a trial in HSCT recipients in the United States would quickly follow, Zeng says. –Elie Dolgin