Allogeneic stem cell transplantation (alloSCT) represents a curative treatment for otherwise fatal hematologic diseases. The curative mechanism relies on immune recognition of hematologic cells in bone marrow and lymphoid organs. Targets are both healthy and malignant cells of the recipient whilst transplanted hematopoietic cells of the donor are spared. The specificity of the immunological procedure therefore consists in recognition of the recipient’s hematopoietic tissue rather than the malignant clones. Specificity is lost if the allo-immune reaction spills over and attacks extra-lymphatic and extra-medullary organs. This allo-immune attack is named “graft-versus-host disease, GVHD” and may cause substantial morbidity and mortality. GVHD comprises a variety of immune-mediated organ dysfunctions and tissue alterations with probably completely different pathomechanisms such as acute and chronic GVHD of different target organs and of different severity.
Studying acute GVHD, our group reported that mortality associates exclusively with non-response to the initial immunosuppressive steroid therapy, which is called (steroid-) refractory GVHD1, 2. Based on a large biobank of longitudinally collected blood samples before and after alloSCT, we decided to investigate “mortality after acute GVHD” as a patient-associated characteristic.
Our results demonstrate that neither the degree of tissue damage nor the strength of the immune attack at disease onset correlate with outcome after acute GVHD2-4. In contrast, endothelial associated stress markers such as soluble thrombomodulin, angiopoietin-2, and IL-8, as well as polymorphisms in the recipient’s thrombomodulin gene associate with mortality after GVHD1, 2, 5, 6. Interestingly, endothelial markers and polymorphisms raised as early prior to conditioning chemotherapy for alloSCT predicted poor survival after acute GVHD. In contrast, the same endothelial markers had no impact on outcome in patients who did not suffer acute GVHD. This phenomenon is called endothelial vulnerability.
During the last years, our group further investigated this endothelial pathomechanism. We identified transplant-associated thrombotic microangiopathy as one endothelial complication coinciding with mortality of acute GVHD. We introduced pravastatin prophylaxis for influencing this pathomechanism and designed an endothelial based clinical score to monitor endothelial distress.
1. Luft T, Dietrich S, Falk C, et al. Steroid-refractory GVHD: T-cell attack within a vulnerable endothelial system. Blood 2011; 118(6): 1685-92.
2. Dietrich S, Falk CS, Benner A, et al. Endothelial vulnerability and endothelial damage are associated with risk of graft-versus-host disease and response to steroid treatment. Biol Blood Marrow Transplant 2013; 19(1): 22-7.
3. Andrulis M, Dietrich S, Longerich T, et al. Loss of endothelial thrombomodulin predicts response to steroid therapy and survival in acute intestinal graft-versus-host disease. Haematologica 2012; 97(11): 1674-7.
4. Luft T, Conzelmann M, Benner A, et al. Serum cytokeratin-18 fragments as quantitative markers of epithelial apoptosis in liver and intestinal graft-versus-host disease. Blood 2007; 110(13): 4535-42.
5. Dietrich S, Okun JG, Schmidt K, et al. High pre-transplant serum nitrate levels predict risk of acute steroid-refractory graft-versus-host disease in the absence of statins. Haematologica 2013.
6. Rachakonda SP, Penack O, Dietrich S, et al. Single-Nucleotide Polymorphisms Within the Thrombomodulin Gene (THBD) Predict Mortality in Patients With Graft-Versus-Host Disease. J Clin Oncol 2014.