CD146 may serve as novel target to treat gastrointestinal GVHD

SAN FRANCISCO — A population of CD146+ and chemokine receptor 5-positive, Th17-prone T cells may serve as an early marker for patients who are at risk for graft-versus-host disease of the gastrointestinal tract, according to study results presented at the ASH Annual Meeting and Exposition.

The presence of these T-cell populations also may suggest that CD146 can be targeted to treat gastrointestinal graft-versus-host disease (GVHD), results showed.

“CD146 is an endothelium receptor… the expression [of which] is increased on activated T cells,” study researcher Wei Li, PhD, assistant professor in the school of health and rehabilitation sciences at Indiana University, said during her presentation at the plenary session. “CCR5 expression on T cells facilitates the importation of CD146 in the gut, and CCR5 blockade inhibits inter-site trafficking in GVHD patients.”

Li and colleagues evaluated plasma samples from patients who underwent hematopoietic stem cell transplantation that were taken 14 days before clinical manifestation of gastrointestinal GVHD. Through proteomic experiments, researchers identified the CD146 protein — which is involved in cell adhesion and trafficking — and the chemokine ligand 14 that binds to the T-cell chemokine receptor 5 (CCR5).

Researchers then sought to evaluate the presence of these proteins at the onset of GVHD symptoms in 214 patients who underwent HSCT. Most of the patients (n=71) had gastrointestinal GVHD, 48 had no GVHD, 33 had non-GVHD enteritis, 22 had skin-first GVHD and 40 had skin-only GVHD.

Patients with gastrointestinal GVHD had significantly more CD146+ and CCR5-positive (CD146⁺CCR5⁺) T cells than patients without GVHD (P˂.0001), with non-GVHD enteritis (P˂.0001) or with skin-only GVHD (P=.007).

High-risk patients with gastrointestinal GVHD — defined as those with a percentage of CD146⁺CCR5⁺ T cells that was higher than the median — were more likely to experience 6-month nonrelapse mortality than low-risk patients (42% vs. 20%; P=.02).

An analysis of samples taken from patients 19 days after HSCT and 14 days before clinical symptoms indicated CD146⁺CCR5⁺ T cells were present before onset of gastrointestinal GVHD.

The T cells in patients with gastrointestinal GVHD expressed a Th1 and Th17 phenotype, as well as a high level of the inducible costimulator (ICOS) involved with the development of Th17 cells. In vitro polarization of CD4 T cells indicated those differentiated with Th17-inducing cytokines and ICOS expressed significantly more CD146⁺CCR5⁺ T cells than those stimulated with Th1-inducing cytokines or CD28 (P˂.001 for both), suggesting CD146+ T cells are Th17-prone.

Researchers then evaluated whether CD146 may serve as a therapeutic target for GVHD. An allogeneic murine GVHD model demonstrated no difference in GVHD severity with donor CD146-/- T cells vs. wild-type CD146+/+ T cells. Further, a xenogeneic GVHD model indicated mice transplanted with CD4+ T cells transduced with CD146 did not lose weight, had similar human T-cell engraftment, had less splenic CD146⁺CCR5⁺ T cells and expressed less T-bet 53 days after HSCT compared with those transduced with a control vector.

“We conclude that the CD146⁺CCR5⁺ T-cell population is a biomarker of gastrointestinal GVHD and has diagnostic and prognostic value,” Li said. “Early measurement of this population in the blood might allow identification of patients at risk of gastrointestinal GVHD and preemptive intervention.”

For more information:

Li W. Abstract #3. Presented at: ASH Annual Meeting and Exposition; Dec. 6-9, 2014; San Francisco.

Disclosure: The researchers report no relevant financial disclosures.