Up-Regulation of alpha4beta7 integrin on peripheral T cell subsets correlates with the development of acute intestinal graft-versus-host disease following allogeneic stem cell transplantation

Abstract

Acute graft-versus-host disease (aGVHD) is a major complication after hematopoietic stem cell transplantation (HSCT). The pathophysiology of aGVHD involves priming of naïve donor T cells in host secondary lymphoid tissue, followed by migration of effector T cells to target organs. Mediators of lymphocyte trafficking are believed to play a significant role in this migration. In this retrospective case-controlled study, we analyzed the expression of alpha4beta7 integrin and CCR9, 2 surface T cell molecules specific for intestinal trafficking, from blood samples collected previously from 59 patients after HSCT (20 without aGVHD, 20 with skin aGVHD, and 19 with intestinal aGVHD). All samples had been obtained before the onset of aGVHD symptoms (with 1 sample collected on the day of symptom onset). Analysis by flow cytometry demonstrated that alpha4beta7 integrin was significantly increased on both naïve and memory T cells in patients who subsequently developed intestinal aGVHD, with the most significant differences observed in memory subsets. Immunohistochemical staining on rectal biopsy specimens from patients with intestinal aGVHD showed that expression of alpha4beta7 integrin was concentrated on mononuclear cells in blood vessels within the intestinal mucosa. These results suggest that alpha4beta7 integrin likely is involved in lymphocyte trafficking in intestinal aGVHD and may have potential clinical use as a correlative biomarker or as a target for the treatment and prophylaxis of intestinal aGVHD after HSCT.

Figure 1

Expression of α4β7 integrin on memory CD4⁺ and CD8⁺ T cells. A, Expression of α4β7 integrin (cells/μL) on memory CD4⁺ T cells. B, Expression of α4β7 integrin (% lymphocytes) on memory CD4⁺ T cells. C, Expression of α4β7 integrin (cells/μL) on memory CD8⁺ T cells. D, Expression of α4β7 integrin (% lymphocytes) on memory CD8⁺ T cells. All values shown are median values. P values from comparisons between groups derived from permutation testing are listed in the text and in Table 2.

Figure 2

Expression of α4β7 integrin on peripheral blood T cell subsets in patients from the control, skin, and gut groups. Thawed mononuclear cells were analyzed for cell surface expression of CD45RO (y-axis) and α4β7 integrin (x-axis). Plots are gated on CD3⁺ lymphocytes based on forward and side scatter and CD3 staining. The numbers indicate the percentage of CD3⁺ lymphocytes for each quadrant. These values are representative patients from within each patient group.

Figure 3

Expression of α4β7 integrin in sigmoid biopsy specimens from patients with intestinal aGVHD. Immunohistochemical staining for α4β7 integrin (brown stain) shows patchy expression of α4β7 integrin on mononuclear cells within the lamina propria (A and B) and as aggregates within small mucosal blood vessels (C, D, and E). Specimens from patients after HSCTwho did not have intestinal aGVHD do not show such staining (F and G). See the Immunohistochemistry section of the text for complete descriptions of techniques and image acquisition information.