GVHD after allogeneic haematopoietic SCT for AML: angiogenesis, vascular endothelial growth factor and VEGF receptor expression in the BM

Abstract

There is increasing evidence suggesting that both angiogenesis and endothelial injury are involved in GVHD. To study the dynamics of angiogenesis, we examined 26 patients with AML who had undergone allogeneic haematopoietic SCT. All were in CR and had either acute GVHD (aGVHD) or chronic GVHD (cGVHD). We performed immunohistochemical studies of BM microvessel density (MVD) using Abs against vascular-endothelial (VE)-cadherin, CD34 and CD105, and expression of vascular endothelial growth factor (VEGF) and its receptors VEGFR-1 and VEGFR-2. At the time of diagnosis, the MVD in AML patients was higher than that in the normal controls, and the MVD decreased after induction chemotherapy. Patients with aGVHD had a significantly higher MVD than patients without aGVHD. Conversely, patients with cGVHD did not have a significantly different MVD. In previous aGVHD, we also found more VEGF þ megakaryocytes. XY FISH in sex-mismatched patients showed that the BM blood vessels consisted mainly of recipient endothelial cells. Taken together, these results suggest that new vessel formation and the VEGF/VEGFR system are involved in aGVHD.

Numerical impairment of nestin+ bone marrow niches in acute GvHD after allogeneic hematopoietic stem cell transplantation for AML

“…13 By contrast, the number of nestin + HSCN was markedly reduced in patients with aGvHD compared with patients without aGvHD (P = 0.04) ( Table 3). In the validation cohort, an increased MVD in patients with any aGvHD or clinically relevant aGvHD (P = 0.001 and 0.007, respectively) was observed, whereas the nestin + HSCN number was reduced (P = 0.05 and 0.09, respectively) (Table 3, Figure 2 and Supplementary Figure S1).…”

“…Whether decreased numbers of nestin + HSCN and increased neovascularization are secondary reactions in response to inflammation or direct GvHD-related processes is currently unknown; however, these characteristics probably represent useful and potentially therapeutically targetable pathways, bypassing pathways related to immunosuppression, and require further clinical studies. 13 …”

“…The patient characteristics of the test cohort and the validation cohort are shown in Table 1; the test cohort was recruited from a previous study collective. 13 Our cohorts met the following inclusion criteria; all patients (1) had AML; (2) had undergone HSCT at our institution between 2004 and 2013; (3) had documented none, acute and/or chronic GvHD (at the time point reported at point 4) diagnosed and graded according to standard criteria; (4) had trephine BM biopsies available from before allo-HSCT and as of the onset of aGvHD (range 1-17 days before the onset of aGvHD) or (for patients who did not have GvHD) 1-4 months after allo-HSCT and after aGvHD resolved or (for patients who did not have GvHD) 6-12 months after allo-HSCT (one missing biopsy at the beginning of the last time point, not at the middle time point, was acceptable); and (5) had AML that was in CR pretransplant at aGvHD and after HSCT. AML was diagnosed according to the World Health Organization criteria.…”

“…Microvessel density (MVD) was assessed as reported elsewhere. 13 The investigators were blinded to the clinical data at the time of immunohistochemical analysis.…”

“…5 Observations with regard to the increased host-derived intramedullar new vessel formation in GvHD provide additional evidence that perturbation of the host-derived stromal/niche components is involved in GvHD-related marrow failure. [11][12][13] Two types of BM niches have been identified in the recent years. The endosteal niche is located along the bony trabeculae and is composed of mainly osteoblasts.…”