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Complement Depletion Improves Human Red Blood Cell Reconstitution in Immunodeficient Mice.

ABSTRACT: We have previously shown that human red blood cells (hRBCs) are subject to robust rejection by macrophages in immunodeficient mice. In this study, we found that mouse serum induces hRBC adherence to murine phagocytic cells, including professional phagocytic macrophages and neutrophils and non-professional phagocytic endothelial cells. Complement was found to be responsible for mouse-serum-induced hRBC adherence to murine phagocytic cells. Although hRBC survival was not improved in NOD/SCID mice with complement depletion by cobra venom factor (CVF), CVF significantly prolonged hRBC survival in mice that were depleted of phagocytic macrophages by clodronate-liposomes. This combination treatment also synergistically improved hRBC reconstitution in human CD34⁺ cell-grafted mice, offering a valuable model to examine human erythropoiesis and RBC function. These data indicate that complement, which might be dispensable for hRBC rejection by macrophages, is critical in hRBC rejection by other types of murine phagocytic cells, such as neutrophils and endothelial cells.

SUBMITTER: Chen B

PROVIDER: S-EPMC5639386 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Complement Depletion Improves Human Red Blood Cell Reconstitution in Immunodeficient Mice.

Chen Bing B Fan Wei W Zou Jun J Zhang Siwen S He Jin J Shu Chang C Zhao Guoqing G Sun Tianmeng T Hu Zheng Z Yang Yong-Guang YG

Stem cell reports 20170928 4

We have previously shown that human red blood cells (hRBCs) are subject to robust rejection by macrophages in immunodeficient mice. In this study, we found that mouse serum induces hRBC adherence to murine phagocytic cells, including professional phagocytic macrophages and neutrophils and non-professional phagocytic endothelial cells. Complement was found to be responsible for mouse-serum-induced hRBC adherence to murine phagocytic cells. Although hRBC survival was not improved in NOD/SCID mice ...[more]

PMID: 28966117

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Project description:Animal models are vital to the study of transfusion and development of new blood products. Post-transfusion recovery of human blood components can be studied in mice, however, there is a need to identify strains that can best tolerate xenogeneic transfusions, as well as to optimize such protocols. Specifically, the importance of using immunodeficient mice, such as NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice, to study human transfusion has been questioned. In this study, strains of wild-type and NSG mice were compared as hosts for human transfusions with outcomes quantified by flow cytometric analyses of CD235a+ erythrocytes, CD45+ leukocytes, and CD41+CD42b+ platelets. Complete blood counts were evaluated as well as serum cytokines by multiplexing methods. Circulating human blood cells were maintained better in NSG than in wild-type mice. Lethargy and hemoglobinuria were observed in the first hours in wild-type mice along with increased pro-inflammatory cytokines/chemokines such as monocyte chemoattractant protein-1, tumor necrosis factor α, keratinocyte-derived chemokine (KC or CXCL1), and interleukin-6, whereas NSG mice were less severely affected. Whole blood transfusion resulted in rapid sequestration and then release of human cells back into the circulation within several hours. This rebound effect diminished when only erythrocytes were transfused. Nonetheless, human erythrocytes were found in excess of mouse erythrocytes in the liver and lungs and had a shorter half-life in circulation. Variables affecting the outcomes of transfused erythrocytes were cell dose and mouse weight; recipient sex did not affect outcomes. The sensitivity and utility of this xenogeneic model were shown by measuring the effects of erythrocyte damage due to exposure to the oxidizer diamide on post-transfusion recovery. Overall, immunodeficient mice are superior models for xenotransfusion as they maintain improved post-transfusion recovery with negligible immune-associated side effects.

Project description:Injuries to peripheral nerves cause loss of motor and sensory function, greatly affecting life quality. Successful repair of the lesioned nerve requires efficient cell debris removal, followed by axon regeneration and reinnervation of target organs. Such process is orchestrated by several cellular and molecular events in which glial and immune cells actively participate. It is known that tissue clearance is largely improved by macrophages, which activation is potentiated by cells and molecules of the acquired immune system, such as T helper lymphocytes and antibodies, respectively. In the present work, we evaluated the contribution of lymphocytes in the regenerative process of crushed sciatic nerves of immunocompetent (wild-type, WT) and T and B-deficient (RAG-KO) mice. In Knockout animals, we found increased amount of macrophages under basal conditions and during the initial phase of the regenerative process, that was evaluated at 2, 4, and 8 weeks after lesion (wal). That parallels with faster axonal regeneration evidenced by the quantification of neurofilament and a growth associated protein immunolabeling. The motor function, evaluated by the sciatic function index, was fully recovered in both mouse strains within 4 wal, either in a progressive fashion, as observed for RAG-KO mice, or presenting a subtle regression, as seen in WT mice between 2 and 3 wal. Interestingly, boosting the immune response by early adoptive transference of activated WT lymphocytes at 3 days after lesion improved motor recovery in WT and RAG-KO mice, which was not ameliorated when cells were transferred at 2 wal. When monitoring lymphocytes by in vivo imaging, in both mouse strains, cells migrated to the lesion site shortly after transference, remaining in the injured limb up to its complete motor recovery. Moreover, a first peak of hyperalgesia, determined by von-Frey test, was coincident with increased lymphocyte infiltration in the damaged paw. Overall, the present results suggest that a wave of immune cell infiltration takes place during subacute phase of axonal regeneration, resulting in transient set back of motor recovery following peripheral axonal injury. Moreover, modulation of the immune response can be an efficient approach to speed up nerve regeneration.

Dataset Information

Complement Depletion Improves Human Red Blood Cell Reconstitution in Immunodeficient Mice.

Publications

Complement Depletion Improves Human Red Blood Cell Reconstitution in Immunodeficient Mice.

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