Chronic Graft-Versus-Host Disease and Systemic Sclerosis: The Same Pathophysiology?,

Abstract 4076

Due to their clinical similarities, controversy has existed as to whether the pathophysiology of chronic graft-versus-host disease (GVHD) and systemic sclerosis (SSc) is the same. The principal cellular effector mechanism in SSc is clonal autoreactive CD4 T lymphocytes that activate fibroblasts, resulting in increased collagen production. We have previously reported that the principal cellular effector mechanism in histocompatible murine chronic GVHD is autoreactive CD4 T lymphocytes, which also stimulated fibroblast collagen production. More recently defects in naturally occurring regulatory T lymphocytes (Treg) have been reported in adult chronic GVHD patients. Using the Miyana classification (Immunity 30:899, 2009), which discriminates between resting Treg lymphocytes, activated Treg lymphocytes, and conventional T lymphocytes (Tcon), we assessed whole blood from pediatric patients, who were more than 1 year following allogeneic hematopoietic stem cell transplantation (HSCT), or patients with active juvenile SSc (jSSc), for their total number of Treg lymphocytes and their relative proportion of resting and activated Treg lymphocytes (r/a ratio).

Normal individuals had an average of 15,300 Treg lymphocytes/mL with 10,890 resting Treg/mL and 4,410 activated Tregs/mL or a r/a ratio of 2.5. The resting Treg lymphocytes were 17.1% of the CD4+, CD25+, CD127- T lymphocytes while the activated Treg lymphocytes were 6.9%. Allogeneic HSCT recipients without a history of either acute or chronic GVHD had elevated numbers of total Treg lymphocytes (25,979/mL) (P=.05) with 19,199 resting and 5,780 activated Treg lymphocytes or a r/a ratio of 3.3, secondary to the relative increase in the proportion of resting Treg lymphocytes. Recipients, who had had only acute GVHD (Grade 2–4) but no history of chronic GVHD, also had an increased number of total Treg lymphocytes with a normal r/a ratio.

Recipients, who had active chronic GVHD, had reduced numbers of total Treg lymphocytes (10,040/mL) (P=.02) with reduced numbers of both resting (7,631/mL) and activated (2,408/mL) Treg lymphocytes. Half of the recipients with active chronic GVHD had more activated Treg lymphocytes than resting T lymphocytes, resulting in an inverted r/a ratio of <1.0. HSCT recipients, who had resolved chronic GVHD, had increased numbers of total Treg lymphocytes (39,342/mL) with increases in both resting (33,325/mL) and activated (6,016/mL) Treg lymphocytes with a r/a ratio of 5.5 due to the relative increase in the proportion of resting Treg lymphocytes.

Patients with jSSc had Treg lymphocyte patterns similar to HSCT recipients with active chronic GVHD; their total number of Treg lymphocytes was reduced (843/mL) (P=.01) with reduced resting (532/mL) and activated (661/mL) Treg lymphocytes and an inverted r/a ratio of 0.8 due to the relative excess of activated Treg lymphocytes. Thus, pediatric patients with either active chronic GVHD or jSSc have reduced total numbers of Treg lymphocytes with a relative increase in the proportion of activated Treg lymphocytes, suggesting that the abnormalities in Treg lymphocytes are central to the pathogenesis of both clinical syndromes. HSCT recipients with a history of resolved chronic GVHD had increased numbers of Treg lymphocytes, indicating that the resolution of chronic GVHD requires increased numbers of Treg lymphocytes with a normal ratio of resting to activated Treg lymphocytes.