Bringing back the help: autologous bone marrow infusion restores CD4+ T cells in AIDS patients with chronic liver disease

Rabson, Arnold B.

doi:10.1038/cddis.2013.373

Cited by 1 publication

(2 citation statements)

References 19 publications

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“…We previously reported that autologous BMT via the hepatic portal vein could effectively reconstitute peripheral CD4 + T-cell counts and hepatic function in splenectomized AIDS patients with decompensated liver cirrhosis 8,9 . To recapitulate this observation in an experimental setting, we induced liver fibrosis with CCl 4 in combination with splenectomy in CD45.2/C57BL/6J mice and examined the subsequent T-cell reconstitution.…”

Section: Resultsmentioning

confidence: 99%

“…Stable reconstitution of CD4 + T-cell number and functional clonality, with complete suppression of viral replication and elimination of viral reservoirs, has been the ultimate goal of AIDS therapy 7 . We previously showed that administration of autologous bone marrow transfusion (BMT) via the hepatic portal vein could effectively restore CD4 + T-cell count in AIDS patients who were also suffering from decompensated liver cirrhosis 8,9 . This observation indicates a possibility that the cirrhotic liver microenvironment may possess lymphopoiesis supportive activity that can direct autologous hematopoietic stem/progenitor cells to undergo differentiation toward early T lineage.…”

Section: Introductionmentioning

confidence: 99%

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Fibrotic liver microenvironment promotes Dll4 and SDF-1-dependent T-cell lineage development

et al. 2019

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The reconstitution of the T-cell repertoire and quantity is a major challenge in the clinical management of HIV infection/AIDS, cancer, and aging-associated diseases. We previously showed that autologous bone marrow transfusion (BMT) via the hepatic portal vein could effectively restore CD4 + T-cell count in AIDS patients also suffering from decompensated liver cirrhosis. In the current study, we characterized T-cell reconstitution in a mouse model of liver fibrosis induced by CCl 4 and found that T-cell reconstitution after BMT via hepatic portal vein was also greatly enhanced. The expression of Dll4 (Delta-like 4), which plays an important role in T-cell progenitor expansion, was elevated in hepatocytes of fibrotic livers when compared to normal livers. This upregulation of Dll4 expression was found to be induced by TNFα in an NFκB-dependent manner. Liver fibroblasts transfected with Dll4 (LF-Dll4) also gained the capacity to promote T-cell lineage development from hematopoietic stem cells (HSCs), resulting in the generation of DN2 (CD4 and CD8 DN 2) and DN3 T-cell progenitors in vitro, which underwent a normal maturation program when adoptively transferred into Rag-2 deficient hosts. We also demonstrated a pivotal role of SDF-1 produced by primary liver fibroblasts (primary LF) in T-lineage differentiation from HSCs. These results suggest that Dll4 and SDF-1 in fibrotic liver microenvironment could promote extrathymic T-cell lineage development. These results expand our knowledge of T-cell development and reconstitution under pathological conditions.

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Section: Resultsmentioning

confidence: 99%