Biology of Blood and Marrow Transplantation
Volume 13, Issue 10 , Pages 1244-1245, October 2007

Alveolar Hemorrhage and Acute Graft-versus-Host Disease

Inserm, Université Paris, Institue Universitaire d’Hématologie, Centre Hayem Hôpital Saint-Louis, Paris, France

Article Outline

 

The very complete study of Majhail et al. [1] on diffuse alveolar hemorrhage (DHA) and infection-associated alveolar hemorrhage (IAH) following hematopoietic stem cell transplantation (HSCT) highlights significant points: the overlap between DAH and IAH in a large series of transplanted patients, the better survival of patients with early-onset alveolar hemorrhage, the allogeneic donor source, and severe acute graft-versus-host disease (aGVHD) as risk factors independently associated with increased incidence of post-HSCT alveolar hemorrhage.

These thoroughly analyzed clinical data are in accordance with the experimental data we obtained in a murine model of allogeneic splenocytes transferred into immunodeficient mice [2]. This model, devoid of conditioning, offers the opportunity to study the cell and tissue lesions induced by the allogeneic reaction, without interference from radiotherapy sequels. We showed that endothelial cells of all organs, including lungs, were early targets of the allogeneic reaction, and that damaged endothelial cells underwent apoptotic death mediated by Fas ligation. In the mice lungs, endothelial damage led to alveolar hemorrhage, associated with lymphocytic bronchitis, a pathologic feature observed in patients with GVHD [3]. Further studies on human biopsies with allogeneic and autologous HSCT showed endothelial lesions and pericapillary hemorrhages linked to severe aGVHD in the upper digestive tract [4]. Another systematic pathologic study of human biopsies showed the reduction of endothelial cell surface in the skin of patients with chronic GVHD (cGVHD)[5]. Because lung biopsies are much more difficult and dangerous to perform than skin and duodenal biopsies, no systematic pathologic study on human lung biopsies has been reported so far. The study of Majhail et al., as a previous report of pulmonary hemorrhage as a cause of death in patients with severe aGVHD [6] supports the fact that, as in the digestive tract, severe aGVHD contributes to hemorrhage in patients’ lungs through endothelial cell damage.

Sequential study in our experimental model showed that endothelial apoptosis is an early damage in the allogeneic reaction, and that all endothelial cells are not at once apoptotic. Therefore, alveolar hemorrhage is focal in early lesions (Figure 1a), limited, as we found in the digestive tract of patients with GVHD, to the areas where endothelial damage has been severe enough to be associated with capillary basal lamina rupture (Figure 1c).Diffuse alveolar damage (Figure 1b) occurs later, and for severe acute allogeneic reactions, induced in our model by transfer of a high number of allogeneic lymphocytes [2]. These experimental data are in accordance with 1 of the main points underlined by Majhail et al. [1]: the difficult distinction between DAH and IAH in HSCT recipients.

  • View full-size image.
  • Figure 1. 

    a, Focal alveolar hemorrhage (arrows) in early lesions of allogeneic reaction; b, diffuse alveolar damage in severe acute allogeneic reaction; and c, ultrastructural aspect of capillary basement membrane rupture (arrows).

The endothelial damage linked to acute allogeneic reaction, if it takes place early in the course of the lung disease, may also contribute to explain the more favorable outcome of early-onset alveolar hemorrhage in this large series of HSCT recipients. Cell death through apoptosis, as observed in target cells of GVHD, does not induce an inflammatory reaction [7]. The vascular endothelium is composed of only 1 layer of endothelial cells, and apoptotic endothelial cells can be cleared by the blood flow [8, 9]. Therefore, endothelial cell repair can more rapidly and efficiently occur after endothelial apoptosis than after whole tissue damage linked to infectious disease. Experimental studies have shown that endothelial repair occurs either through local migration and proliferation of endothelial cells adjacent to the site of injury, or through homing and incorporation of bone marrow-derived endothelial progenitor cells on the site of endothelial injury [8, 9]. Although endothelial cell division, which may reach 50% of the cells in and around the injured sites after induced arterial denudation [10], might be active in GVHD patients, the role of bone marrow-derived cells has been recently emphasized. Endothelial cells of donor origin were found in 2 sequential series of transbronchial biopsies of HSCT patients [11]. In skin biopsies we only found donor-derived endothelial cells in HSCT patients with GVHD, and the number of chimeric cells was linked to the severity of GVHD-induced cell damage [12]. Particularly relevant to the GVHD-induced apoptotic damage is the recent in vitro demonstration that apoptotic bodies from endothelial cells enhance the number and initiate the differentiation of human endothelial progenitor cells in vitro [13].

As stated by Majhail et al. [1], the current etiopathogenic paradigm for DAH is based on nontransplantation DAH in systemic vasculitides and collagen vascular disease. Even on these DAH nonrelated to transplantation, no pathologic study of early events is available in humans. Therefore, systematic studies of pure allogeneic reactions induced in animal models could help to identify the participation of aGVHD in the alveolar hemorrhages following HSCT.

Back to Article Outline

References 

  1. Majhail NS, Parks K, Defor TE, et al. Diffuse alveolar hemorrhage and infection-associated alveolar hemorrhage following hematopoietic stem cell transplantation: related and high-risk clinical syndromes. Biol Blood Marrow Transplant. 2006;12:1038–1046
  2. Janin A, Deschaumes C, Daneshpouy M, et al. CD95 engagement induces disseminated endothelial cell apoptosis in vivo: immunopathologic implications. Blood. 2002;99:2940–2947
  3. Yousem SA. The histological spectrum of pulmonary graft-versus-host disease in bone marrow transplant recipients. Hum Pathol. 1995;26:668–675
  4. Ertault-Daneshpouy M, Leboeuf C, Lemann M, et al. Pericapillary hemorrhage as criterion of severe human digestive graft-versus-host disease. Blood. 2004;103:4681–4684
  5. Biedermann BC, Sahner S, Gregor M, et al. Endothelial injury mediated by cytotoxic T lymphocytes and loss of microvessels in chronic graft versus host disease. Lancet. 2002;359:2078–2083
  6. Wojno KJ, Vogelsang GB, Beschorner WE, et al. Pulmonary hemorrhage as a cause of death in allogeneic bone marrow recipients with severe acute graft-versus-host disease. Transplantation. 1994;57:88–92
  7. Granville DJ, Carthy CM, Hunt DW, et al. Apoptosis: molecular aspects of cell death and disease. Lab Invest. 1998;78:893–913
  8. Woywodt A, Bahlmann FH, De Groot K, et al. Circulating endothelial cells: life, death, detachment and repair of the endothelial cell layer. Nephrol Dial Transplant. 2002;17:1728–1730
  9. Woywodt A, Haubitz M, Buchholz S, et al. Counting the cost: markers of endothelial damage in hematopoietic stem cell transplantation. Bone Marrow Transplant. 2004;34:1015–1023
  10. Ingram DA, Caplice NM, Yoder MC. Unresolved questions, changing definitions, and novel paradigms for defining endothelial progenitor cells. Blood. 2005;106:1525–1531
  11. Spencer H, Rampling D, Aurora P, et al. Transbronchial biopsies provide longitudinal evidence for epithelial chimerism in children following sex mismatched lung transplantation. Thorax. 2005;60:60–62
  12. Murata H, Janin A, Leboeuf C, et al. Donor-derived cells and human graft-versus-host disease of the skin. Blood. 2006;109:2663–2665
  13. Hristov M, Erl W, Linder S, et al. Apoptotic bodies from endothelial cells enhance the number and initiate the differentiation of human endothelial progenitor cells in vitro. Blood. 2004;104:2761–2766

PII: S1083-8791(07)00334-5

doi:10.1016/j.bbmt.2007.06.014

Refers to article:

  • Diffuse Alveolar Hemorrhage and Infection-Associated Alveolar Hemorrhage following Hematopoietic Stem Cell Transplantation: Related and High-Risk Clinical Syndromes

    Navneet S. Majhail, Kristi Parks, Todd E. Defor, Daniel J. Weisdorf
    Biology of Blood and Marrow Transplantation October 2006 (Vol. 12, Issue 10, Pages 1038-1046)

Biology of Blood and Marrow Transplantation
Volume 13, Issue 10 , Pages 1244-1245, October 2007

Article Tools

* Image Usage & Resolution