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Open Access Publications from the University of California

Scholarly Works (4 results)

  • Article
  • Peer Reviewed
UCLA Previously Published Works (2015)

Purpose of review

This review summarizes the phenotype and function of macrophages in the context of solid organ transplantation and will focus on fundamental insights into their paradoxical pro-inflammatory versus suppressive function. We will also discuss the therapeutic potential of regulatory macrophages in tolerance induction.

Recent findings

Macrophages are emerging as an essential element of solid organ transplantation. Macrophages are involved in the pathogenesis of ischemia reperfusion injury, as well as both acute and chronic rejection, exacerbating injury through secretion of inflammatory effectors and by amplifying adaptive immune responses. Notably, not all responses associated with macrophages are deleterious to the graft, and graft protection can in fact be conferred by macrophages. This has been attributed to the presence of macrophages with tissue-repair capabilities, as well as the effects of regulatory macrophages.

Summary

The explosion of new information on the role of macrophages in solid organ transplantation has opened up new avenues of research and the possibility of therapeutic intervention. However, the role of myeloid cells in graft rejection, resolution of rejection and tissue repair remains poorly understood. A better understanding of plasticity and regulation of monocyte polarization is vital for the development of new therapies for the treatment of acute and chronic transplant rejection.
    Cover page: The divergent roles of macrophages in solid organ transplantation
    • Thesis
    • Peer Reviewed
    UCLA Electronic Theses and Dissertations (2016)

    Rejection remains a major challenge to successful organ transplantation. Central to the immune response to the allograft are antibodies reactive to donor human leukocyte antigen (HLA) molecules which trigger acute and chronic antibody-mediated rejection (AMR) and contribute to graft loss. HLA class I antibody-induced injury to the allograft endothelium recruits monocytes, which have been implicated as seminal players in the process of allograft rejection. Recent studies suggest that mTOR inhibitors modulate leukocyte recruitment to endothelium in models of inflammation. As such, we investigated the role of mTOR signaling in monocyte recruitment in HLA class I-induced acute AMR. First, we used an in vitro system of HLA I-stimulated human primary endothelial cells pre-treated with mTOR inhibitors and found that mTOR is a key regulator of monocyte binding to the endothelium. This finding was confirmed in an in vivo murine model of acute AMR, in which MHC I antibody-induced endothelial injury and monocyte infiltration in the graft were significantly reduced with administration of the mTOR inhibitor rapamycin. Additionally, rapamycin treatment blocked phosphorylation of mTOR proteins downstream of HLA I signaling in endothelium. To elucidate the mechanisms responsible for this process we studied the effects of mTOR inhibition on the expression and function of adhesion molecules on the cell surface of HLA I-stimulated endothelial cells. Monocytes firmly adhere to the endothelium via ICAM-1 engagement. mTOR inhibition in HLA I-stimulated endothelial cells impaired ICAM-1 function and hampered the capacity of endothelium to support firm adhesion of monocytes. Next, we explored the requirement of mTOR signaling in monocyte activation and adherence to HLA I-stimulated endothelium. mTOR modulates monocyte activation and adhesiveness following PSGL-1 crosslinking. To conclude, we found mTOR inhibition dampens endothelial activation in response to HLA I antibodies as well as monocyte activation following PSGL-1 engagement, and prevents monocytic infiltration into cardiac allografts. These findings can be translated to the clinical setting, providing the rationale for the application of mTOR inhibitors for mitigating the risks of AMR.

      Cover page: The Mechanisms of mTOR-mediated Monocyte Recruitment to HLA Class I Antibody-Activated Endothelial Cells
      • Article
      • Peer Reviewed
      UCLA Previously Published Works (2012)

      Background

      Modifications of adjuvants that induce cell-mediated over antibody-mediated immunity is desired for development of vaccines. Nanocapsules have been found to be viable adjuvants and are amenable to engineering for desired immune responses. We previously showed that natural nanocapsules called vaults can be genetically engineered to elicit Th1 immunity and protection from a mucosal bacterial infection. The purpose of our study was to characterize immunity produced in response to OVA within vault nanoparticles and compare it to another nanocarrier.

      Methodology and principal findings

      We characterized immunity resulting from immunization with the model antigen, ovalbumin (OVA) encased in vault nanocapsules and liposomes. We measured OVA responsive CD8(+) and CD4(+) memory T cell responses, cytokine production and antibody titers in vitro and in vivo. We found that immunization with OVA contain in vaults induced a greater number of anti-OVA CD8(+) memory T cells and production of IFNγ plus CD4(+) memory T cells. Also, modification of the vault body could change the immune response compared to OVA encased in liposomes.

      Conclusions/significance

      These experiments show that vault nanocapsules induced strong anti-OVA CD8(+) and CD4(+) T cell memory responses and modest antibody production, which markedly differed from the immune response induced by liposomes. We also found that the vault nanocapsule could be modified to change antibody isotypes in vivo. Thus it is possible to create a vault nanocapsule vaccine that can result in the unique combination of immunogen-responsive CD8(+) and CD4(+) T cell immunity coupled with an IgG1 response for future development of vault nanocapsule-based vaccines against antigens for human pathogens and cancer.
        Cover page: Vault Nanocapsules as Adjuvants Favor Cell-Mediated over Antibody-Mediated Immune Responses following Immunization of Mice
        • Article
        • Peer Reviewed
        UCLA Previously Published Works (2018)
        Antibody-mediated rejection (AMR) resulting in transplant allograft vasculopathy (TAV) is the major obstacle for long-term survival of solid organ transplants. AMR is caused by donor-specific antibodies to HLA, which contribute to TAV by initiating outside-in signaling transduction pathways that elicit monocyte recruitment to activated endothelium. Mechanistic target of rapamycin (mTOR) inhibitors can attenuate TAV; therefore, we sought to understand the mechanistic underpinnings of mTOR signaling in HLA class I Ab-mediated endothelial cell activation and monocyte recruitment. We used an in vitro model to assess monocyte binding to HLA I Ab-activated endothelial cells and found mTOR inhibition reduced ezrin/radixin/moesin (ERM) phosphorylation, intercellular adhesion molecule 1 (ICAM-1) clustering, and monocyte firm adhesion to HLA I Ab-activated endothelium. Further, in a mouse model of AMR, in which C57BL/6. RAG1-/- recipients of BALB/c cardiac allografts were passively transferred with donor-specific MHC I antibodies, mTOR inhibition significantly reduced vascular injury, ERM phosphorylation, and macrophage infiltration of the allograft. Taken together, these studies indicate mTOR inhibition suppresses ERM phosphorylation in endothelial cells, which impedes ICAM-1 clustering in response to HLA class I Ab and prevents macrophage infiltration into cardiac allografts. These findings indicate a novel therapeutic application for mTOR inhibitors to disrupt endothelial cell-monocyte interactions during AMR.
          Cover page: Outside-in HLA class I signaling regulates ICAM-1 clustering and endothelial cell-monocyte interactions via mTOR in transplant antibody-mediated rejection
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