Immunological and Regenerative Aspects of Hepatic Mast Cells in Liver Allograft Rejection and Tolerance

Abstract

The precise roles of mast cells in liver allograft rejection and tolerance are still unknown. This study aimed to explore the roles of mast cells in immune regulation and liver regeneration for tolerance induction by using rat models of orthotopic liver transplantation (OLT). Stem cell factor (SCF) and its receptor c-Kit, which are critical to the migration and development of not only stem cells but also mast cells, significantly increased in the tolerogenic livers as compared with rejected livers. The significant elevation of mast cell tryptase, high-affinity IgE receptor, and histamine suggested the activation of mast cells in liver allografts at the tolerogenic phase after OLT. Immunohistochemical analysis using confocal microscope clearly showed colocalization of mast cells, Foxp3+ Tregs, γδ T cells, and recipient-derived hepatic progenitor cells with higher expression of SCF, IL-9, IL-10, TGF-β1, and IL-17 related to immunoregulation and liver regeneration in the donor grafts of a tolerogenic OLT model. Cross-talk among mast cells and other cells was evaluated by in vitro studies demonstrating that syngeneic bone marrow−derived mast cells (BMMCs) co-cultured with naïve splenocytes or primary hepatocytes significantly increased the population of splenic γδ T cells by mitogen stimulation or by mast cell degranulation, and also significantly induced the hepatocyte proliferation, respectively. Our results suggested that mast cells in the donor grafts may play important roles in the induction/maintenance of immune tolerance and liver regeneration resulting in the replacement of hepatic cells from donor to recipient.

Isolation and characterization of hepatic mast cells from cholestatic rats

“…BDL induces ductal proliferation in response to the injured duct(20, 27), and subsequently there is an infiltration of mast cells beginning approximately 2–3 days post-BDL shown in Figure 1. In support of our findings, mast cells are also found in other models of liver injury and repair including following carbon tetrachloride treatment(28), alcohol feeding(29) and during liver regeneration(30). Since mast cells do not mature and differentiate until they reach their tissue of destination, the contents of mast cells may differ between the liver and other organs(25).…”

“…It has also been noted that mast cells may play a role in allograft rejection during liver resection or transplantation. In this study, the authors found that a crosstalk exists between mast cells other cells including hepatocytes and induction of mast cell degranulation induces hepatocyte proliferation, thus contributing positively to cellular repopulation and liver regeneration(30). Similar to our findings, mast cells have been noted to increase in number during PSC progression(7, 33) in both rodent models and human tissues.…”

Level of Transforming Growth Factor Beta-1 Relates to Congenital Liver Disease Severity in Children of Early Age

“…Экспериментальные исследования на моделях спонтанной иммунной толерантности трансплантата печени у мышей показывают, что после трансплантации в донорской печени увеличи-вается количество регуляторных Foxp3+ и γδ Т-кле-ток, что сопровождается увеличением продукции ряда цитокинов, в том числе и TGF-β [8,9]. Кли-нические наблюдения, проведенные Briem-Richter с соавторами [10], выявили тенденцию к повышению уровня TGF-β1 в сыворотке крови реципиентов с хорошей функцией трансплантата печени.…”

Mast cell-derived serine proteinase regulates T helper 2 polarization

“…Mast cells play a critical role in the establishment of the organ or tissue transplantation tolerance23. Yet, whether mast cells play a role in regulation of the T helper (Th)2 response is unknown.…”