A5041669374- T-cell and B-cell Immunology
- Immune Cell Function and Interaction
- Renal Transplantation Outcomes and Treatments
- Immunotherapy and Immune Responses
- Cytomegalovirus and herpesvirus research
- Xenotransplantation and immune response
- Cell Adhesion Molecules Research
- Transplantation: Methods and Outcomes
- Tissue Engineering and Regenerative Medicine
- Electrospun Nanofibers in Biomedical Applications
- Herpesvirus Infections and Treatments
- CAR-T cell therapy research
- Adenosine and Purinergic Signaling
- Pancreatic function and diabetes
- Diabetes and associated disorders
- HIV Research and Treatment
- Infectious Aortic and Vascular Conditions
- Neonatal Health and Biochemistry
- Monoclonal and Polyclonal Antibodies Research
- Organ Donation and Transplantation
- Galectins and Cancer Biology
- Immune Response and Inflammation
- Organ Transplantation Techniques and Outcomes
- Bone Tissue Engineering Materials
- Toxin Mechanisms and Immunotoxins
Nationwide Children's Hospital
2018-2024
University of Pittsburgh
2011-2016
T cell Ig domain and mucin protein 1 (TIM-1) is a costimulatory molecule that regulates immune responses by modulating CD4+ effector differentiation. However, the function of TIM-1 on other populations unknown. Here, we show in vivo mice, predominantly expressed B rather than cells. Importantly, was large majority IL-10–expressing regulatory cells all major subpopulations, including transitional, marginal zone, follicular cells, as well population characterized CD1dhiCD5+. A low-affinity...
Maturation of T cell–activating APCs directly links innate and adaptive immunity is typically triggered by microbial infection. Transplantation allografts, which are sterile, generates strong cell responses; however, it unclear how grafts induce APC maturation in the absence microbial-derived signals. A widely accepted hypothesis that dying cells graft release “danger” molecules initiate alloimmune response. Here, we demonstrated danger signals associated with not sufficient to alloimmunity,...
Abstract Successful engraftment of organ transplants has traditionally relied on preventing the activation recipient (host) T cells. Once T-cell occurred, however, stalling rejection process becomes increasingly difficult, leading to graft failure. Here we demonstrate that graft-infiltrating, dendritic cells (DCs) play a key role in driving transplanted organs by activated (effector) We show donor DCs accompany heart or kidney grafts are rapidly replaced DCs. The originate from non-classical...
The migration of effector or memory T cells to the graft is a critical event in rejection transplanted organs. prevailing view that key steps involved cell - integrin-mediated firm adhesion followed by transendothelial are dependent on activation Gαi-coupled chemokine receptors cells. In contrast this view, we demonstrated vivo cognate antigen was necessary for and CD8+ specific antigens both occurred independent Gαi signaling. Presentation either endothelial bone marrow-derived APCs extend...
Our understanding of tissue-resident memory T (T
Abstract Adoptive cell therapy (ACT), especially with CD4+ regulatory T cells (CD4+ Tregs), is an emerging therapeutic strategy to minimize immunosuppression and promote long-term allograft acceptance, although much research remains realize its potential. In this study, we investigated the potency of novel Ab-suppressor CXCR5+CD8+ (CD8+ TAb-supp) in comparison conventional CD25highFoxp3+CD4+ Tregs for suppression humoral alloimmunity a murine kidney transplant (KTx) model Ab-mediated...
Aim: To characterize early events in neotissue formation during the first 2 weeks after vascular scaffold implantation. Materials & methods: Biodegradable polymeric scaffolds were implanted as abdominal inferior vena cava interposition grafts wild-type mice. Results: All explanted at day 1 contained a platelet-rich mural thrombus. Within few days, majority of cell infiltration appeared to be from myeloid cells peritoneal surface with modest along lumen. Host reaction graft was distinct...
Wall stress is often lower in tissue-engineered constructs than comparable native tissues due to the use of stiff polymeric materials having thicker walls. In this work, we sought design a murine arterial graft more favorable local mechanical environment for infiltrating cells; used electrospinning enclose compliant inner core poly(glycerol sebacate) with stiffer sheath poly(caprolactone) reduce potential rupture. Two scaffolds were designed that differed thickness as previous computational...
CCR5 KO kidney transplant (KTx) recipients are extraordinarily high alloantibody producers and develop pathology that mimics human antibody-mediated rejection (AMR). C57BL/6 mice (H-2b) were transplanted with A/J kidneys (H-2a); select cohorts received adoptive cell therapy (ACT) alloprimed CXCR5+CD8+ T cells (or control cells) on day 5 after KTx. ACT efficacy was evaluated by measuring posttransplant alloantibody, pathology, allograft survival. Recipients assessed for the quantity of...
Human cytomegalovirus (HCMV) donor positive (D+) serostatus with acute rejection is associated renal allograft loss, but the impact of recipient (R+) unclear. In an allogeneic transplant model, antiviral natural killer (NK) and CD8+ T cell memory responses in murine CMV (MCMV) D+/R+ transplants were compared to D-/R- D+/R- transplants, infection varied by MCMV dose strain. had high primary cytolytic (interferon-γ+) cytotoxic (granzyme B+) NK responses, whereas lower recipients receiving a...
Human cytomegalovirus (CMV) infection is associated with renal allograft dysfunction and loss, particularly in combination acute rejection. Emerging literature suggests that non-HLA antibodies may contribute to antibody-mediated rejection, but pathogen-induced have not been investigated this context. This study examines the presence of CMV-induced murine CMV (MCMV)-infected allografts during rejection.Intragraft immunoglobulin G (IgG) complement C3 immunostaining were compared among...
ABSTRACT Cytomegalovirus (CMV) infection is associated with renal allograft failure by unknown mechanisms. In a murine transplant model, CMV (MCMV) induces intragraft infiltration of Th17 cells co-expressing Th1 cytokines, IFN-γ and TNF-α, but only minority are specific for MCMV antigens. Instead, promotes viral antigen-independent cell recruitment via CCL20-CCR6 CXCL10-CXCR3 interactions. correlate directly frequencies inversely Tregs in infected grafts. Pharmacologic inhibition IL-17A...
Abstract Purpose CCR5 KO kidney transplant (KT) mice produce high titer alloantibody (alloAb) associated with severe antibody-mediated rejection (AMR) that reproduces AMR histology observed in human KT recipients. We previously reported the novel alloAb suppressor activity of alloprimed CXCR5+IFNγ+CD8+ T (Tab-supp) cells following hepatocellular mice. Here, we investigated biologic impact CD8+ Tab-supp and their capacity to suppress adoptive cell transfer (ACT) into Methods (H-2b) were...
Abstract Donor DC exit organ grafts after transplantation and are replaced by host DC. The origin function of these tissue-resident, however is unknown. Using flow cytometry 2-photon intravital microscopy, we observed rapid replacement donor in both syngeneic allogeneic heart kidney within 3 days transplantation, demonstrated that the vast majority were monocyte-derived (Mono-DC). By day 7, allografts harbored >5-fold more than syn >45-fold native tissue. Enhanced accumulation...
Abstract Host effector T cell graft infiltration is a key step in the pathogenesis of both acute and chronic rejection. Recent data indicate migration into primary vascularized organ transplants such as heart kidney driven by donor antigen recognition, not via Gai-coupled chemokine receptor signaling. Whether it true for neovascularized pancreatic islet allografts unknown. We co-transferred pertussis toxin (Ptx)-treated untreated TCR-tg (OT-1) cells B6 recipients 7-10 days after...
Donor DC exit organ grafts after transplantation and are replaced by host DC. The origin function of these tissue-resident, however is unknown. Using flow cytometry 2-photon intravital microscopy, we observed rapid replacement donor in both syngeneic allogeneic heart kidney within 3 days transplantation, demonstrated that the vast majority were monocyte-derived (Mono-DC). By day 7, allografts harbored >5-fold more than syn >45-fold native tissue. Enhanced accumulation was inhibited treating...
Abstract It is generally assumed that inflammation or ‘danger’ at the time of transplantation triggers rejection. Here we tested alternate hypothesis innate immune system distinguishes between self and allogeneic non-self, causing DC maturation initiation adaptive immunity. B6 Rag-/-γc-/- CX3CR1-GFP+/- reporter mice, which lack T, B, NK cells, received syngeneic (B6) (Balb/c) vascularized heart grafts. >90% DCs present in grafts by d.1 after Tx were derived from host monocytes....
Microcomputed tomography (microCT) angiography is an invaluable resource to researchers. New advances in this technology have allowed for high-quality images be obtained of micro-vasculature and are high-fidelity tools the field organ transplantation. In model orthotopic liver transplantation (OLT) mice, microCT affords opportunity evaluate allograft anastomosis real time has added benefit not having sacrifice study animals. The choice contrast, as well image acquisition settings, create a...
Abstract A key step in rejection is the transendothelial migration (TEM) of Ag-specific effector and memory (E&M) T cells into graft. It assumed that this mediated by Gαi-coupled chemokine receptor signaling. This migratory paradigm was revisited treating Ag(OVA)-specific(OT-I) non-specific(P14) CD8 E&M with pertussis toxin (PTx) to block Gαi signaling or not co-transferring B6 recipients Act-OVA wt vascularized allografts investigate roles cognate Ag cell TEM. Flow cytometry...
Background: A key step in the rejection process is transendothelial migration of Ag-specific effector and memory T cells into graft. It generally assumed that this mediated by Gai-coupled chemokine receptor signaling. Here, we revisited paradigm investigating polyclonal monoclonal to vascularized transplants presence or absence Gai Methods: B6 CD4 CD8 primed against BALB/c were treated with pertussis toxin (PTx) block signaling not co-transferred wt alymphoplastic (aly/aly) mice 2 days after...
Abstract Kidney transplant (KTx) into CCR5 KO mice is an excellent model to study AMR immunobiology due a heightened humoral response posited be secondary impaired CD4+Treg cell trafficking the allograft. We have observed that adoptive therapy (ACT) with alloprimed CXCR5+CD8+ T cells mediates significant reduction of alloAb titer in KTx recipients. hypothesized are more potent inhibitors production than CD4+Tregs. found recipients significantly fewer (782±183 vs 2058±167 cells/mm3) and...
Abstract CXCR5+CD8+TAb-supp cells inhibit alloantibody (alloAb) production, AMR, and prolong graft survival in mouse models. To determine if this cell therapy is compatible with standard immunosuppression (IS) strategies, we investigate the interaction of CD8+ TAb-supp adoptive (ACT) IS [mTOR inhibitors (mTORi) or CNi] a model kidney transplant (KTx). CXCR5+CD8+ T ACT to CCR5 KO recipients on day 1 after KTx (D1) significantly suppresses D14 alloAb titer (1259±114) versus untreated controls...