CYTOTOXIC FOLLICULITIS IN GVHD - EVIDENCE OF FOLLICULAR STEM-CELL INJURY AND RECOVERY

Recent observations indicate that stem cells of the murine hair follicle exist exclusively as a subpopulation of relatively undifferentiated outer root sheath cells located in the bulge region at the mid-portion of the follicle. Because it has been hypothesized that stem cells of interfollicular epidermis may represent targets of cytotoxic responses in acute graft-versus-host disease (AGVHD), we studied murine AGVHD and observed sequential skin biopsies for the presence and evolutionary pattern of follicular injury. Highly purified subsets of donor T cells were used to produce AGVHD to multiple minor histocompatibility (H) antigens in two strain combinations of mice matched for the major histocompatibility complex (MHC). In the C3H.SW- > B6 strain combination, only CD8+ effector cells produced histologic evidence in skin of AGVHD, which peaked three weeks post-transplant. In the B10.D2- > DBA/2 strain combination, CD4+ effector cells, and to a lesser extent, CD8+ cells, mediated disease, which peaked during the fourth week post-transplant. Analysis of skin from both strain/effector cell combinations revealed follicular infiltrates preferentially involving follicular stem cell (FSC) regions (bulge) of anagen follicles between the second and third weeks post-transplant. These infiltrates often preceded infiltration of adjacent interfollicular epidermis and were associated with follicular involution to telogen (resting) phase. By the fourth week post-transplant, > 50% of follicles were in telogen phase and residual inflammation was minimal. This provided a unique opportunity to observe follicular recovery from telogen. This involved formation of buds of premordial hair matrix derived from FSC populations of the bulge regions, and subsequent descent of these buds, initially tethered by elongate columns of putative stem cell progeny, along the course of fibrous tracts corresponding to follicular sheaths. These findings suggest that stem cells of hair follicles, as well as epidermis, represent potential targets of cytotoxicity in AGVHD. Moreover, they provide in vivo demonstration that the newly-described FSC population of the follicular bulge give rise to germinative matrix epithelium upon pathological stimulation.