Early Th1 Immunity Decreases Acute Graft-Versus-Host Disease and Impairs Graft-Versus-Leukemia Effect after Allogeneic Hematopoietic Cell Transplantation

Donor Th1 immunity can initiate acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic cell transplantation (HCT). Paradoxically, deficiency of the Th1 cytokine IFN-g can accelerate aGVHD in animal models. We hypothesized that Th1 cells can be inflammatory (pro-GVHD) or inhibitory (anti-GVHD/GVL) depending on their expression of tissue-homing molecules.

From February 2007 to March 2009, patients undergoing HCT were eligible for an aGVHD biomarker trial at Vanderbilt University. Circulating Th1 cells (CD4+ IFN-g+) were quantified in 59 patients at neutrophil engraftment using flow cytometry. Circulating skin-homing (CLA+), gut-homing (α4β7+), and conventional (CLA-α4β7-) Th1 cells were identified and expressed as a percentage of the total Th1 population.

Table 1 details the patient characteristics (N=59). Grade 2-4 or 3-4 aGVHD was diagnosed in 46 (78%) and 9 (15%) patients, respectively. Patients developing grade 2-4 aGVHD had significantly lower percentages of total Th1 cells at engraftment compared to recipients with grade 0-1 aGVHD (P=0.03) (Table 2). Decreasing frequencies of total Th1 cells predicted increasing severity of aGVHD (OR 1.12; P=0.01). However, when accounting for tissue-specificity, patients with grade 2-4 aGVHD had increased frequencies of circulating skin-homing (CLA+) Th1 cells (P<0.01) and gut-homing (α4β7+) Th1 cells (P=0.07) but lower conventional (CLA- α4β7-) Th1 cells (P=0.03), than patients with grade 0-1 aGVHD (Table 2). The percentage of CLA+ Th1 cells was also higher in patients with skin-only aGVHD (4.1% vs. 2.8%; P=0.05). Adjusting for donor, conditioning, and stem cell source, lower percentage of total Th1 cells at engraftment was associated with increased risk for grade 2-4 aGVHD (HR 1.07; P=0.02). Conversely, increasing percentage of total Th1 cells at engraftment was associated with inferior DFS, when analyzed as a continuous variable (HR 1.06; P=0.05) or categorical variable (Figure 1) (independent of age and disease risk). aGVHD did not impact survival.

Early Th1 cell expansion within the CLA- α4β7- compartment decreases alloreactivity perhaps due to impaired T cell migration to target tissue. High percentages of Th1 cells at engraftment can identify patients who may benefit from pre-emptive therapies to promote GVL and prevent malignancy relapse.

Table 1.

Variable	N (%)
Age	47 y (21-70)
Male	29 (49)
Disease risk
Standard	29 (49)
High	30 (51)
Conditioning
Ablative	33 (56)
Reduced intensity	26 (44)
Donor
Related	43 (72)
Unrelated	16 (28)
Stem cell
Peripheral blood	49 (83)
Other	10 (17)

Table 2. Median percentage of Th1 subsets at engraftment (range)

	Grade 0-1 aGVHD	Grade 2-4 aGVHD	P
Total (parent) Th1 cells	15.1% (2.1-28.8)	76.6% (39.5-94.1)	0.03
CLA+ Th1 cells	1.0% (0.2-3.5)	2.9%   (0.4-11.2)	<0.01
α4β7+ Th1 cells	22.3% (5.7-59)	31.8% (12.7-43.6)	0.07
CLA- α4β7- Th1 cells	76.6% (39.5-94.1)	64.9% (47.3-82.9)	0.03