Target Antigens Determine Graft-versus-Host Disease Phenotype

Abstract

Chronic graft-vs-host disease (cGVHD) is an increasingly frequent complication of allogeneic stem cell transplantation. Phenotypically, cGVHD differs from patient to patient; in particular, a subset of patients develops extensive cutaneous fibrosis. Similarly, graft-vs-host disease (GVHD) is distinct in inbred murine donor:recipient pairings, indicating a genetic component to disease phenotype. The B10.D2 → BALB/c (H-2d) strain pairing uniquely recapitulates key pathologic features of fibrotic human cutaneous cGVHD. To distinguish whether this genetic component is due to differences in genes that modulate immune responses or to the specific Ags targeted, we asked whether skin-dominant cGVHD also develops in the B10 → BALB.B (H-2b) and B10.BR → BALB.K (H-2k) MHC-congenic pairings. Because each MHC haplotype presents different peptides and selects different T cell repertoires, GVHD in each donor:recipient pair undoubtedly targets different Ags. We found that, in contrast to BALB/c recipients, BALB.B mice never manifested skin disease while BALB.K mice developed a modified form of skin disease. Instead, BALB.B and BALB.K recipients developed systemic GVHD which was absent in BALB/c mice. Moreover, in (B10 × B10.D2)F1 → (BALB.B × BALB/c)F1 H-2b/d transplants, recipients developed both cutaneous and systemic disease. Thus, the selection of immunodominant Ags determines the target and character of GVHD, providing insight into the genetic basis for different forms of GVHD.

Spleen tyrosine kinase (Syk) is a potent target for GvHD prevention at different cellular levels

“…GvHD severity was determined according to a previously published histopathology scoring system. 23 Tumor models…”

New perspectives on the biology of acute GVHD

“…Thus, different mHAs might dictate variable phenotype, target organ involvement, development kinetics of GVHD and antitumor responses after allogeneic BMT. 11 Some mHAs, such as HA-1, HA-2, HB-1 and BCL2A1, are primarily found on hematopoietic cells, whereas others such as the H-Y antigens, HA-3, HA-8 and UGT2B17 are ubiquitous. 12 It is important to note that not all mHAs are equivalent in terms of inducing an immune response.…”

CD8+ but not CD4+ T cells require cognate interactions with target tissues to mediate GVHD across only minor H antigens, whereas both CD4+ and CD8+ T cells require direct leukemic contact to mediate GVL

“…without knowledge as to experimental group as we have described. 15 Images of bowel and liver were obtained with an Olympus BX40 microscope (Olympus America, Lakewood, CO) using a 10ϫ eyepiece and an 20ϫ objective, with a QImaging QColor5 camera (Olympus) and QCapture software (Olympus). Images were processed with Adobe Photoshop 7.0 software (Adobe Systems, San Jose, CA).…”