Publications

Abstract

Vascularized Composite Allotransplantation (VCA) is an important therapeutic option for patients that incur debilitating injuries to the face or limbs. The complexity and immunogenicity of tissue types within VCA grafts pose unique challenges and necessitate the use of intensive immunosuppression; however, graft rejection remains a challenge in VCA.Deep proteomic profiling and high dimensional analysis with cytometry time of flight were used to define the cell types and effector mechanisms elicited by VCA in BALB/c (H-2Kd) > C57BL/6 (H-2Kb) limb recipients. Spleen and cervical draining lymph nodes were collected post-transplant days 1, 3, 5, and 7 (n =4-6 mice/group/day). We identified dynamic, coordinated signatures in T cell and monocyte populations associated with VCA allograft rejection.In comparison to syngeneic transplant recipients, allogeneic recipients exhibited significant alterations in the immune cell populations within secondary lymphoid tissues. These changes included very early expansion of double-negative TCRβ- T cells, including IL-17A-producing γδ T cells, and patrolling monocytes. Subsequently, CD8+CD62L+ T cells and CD8+ effector/effector memory T cells (Teff/Tem), Ly6ChiCCR2hiCX3CR1low classical monocytes, CD4+ Teff/Tem, and CD8+CD25hiCCR7low Teff/Tem were increased by day 5. CD8+CD25hiCCR7low Teff/Tem with the highest expression of IFN-γ, perforin, and granzyme B were enriched by day 7.High dimensional proteomic analysis reveals multiple innate and Teff/Tem subsets in acute rejection following VCA. In particular, IL-17A-producing γδ T cells and classical monocytes may be particularly important in initiating the alloimmune response in VCA recipients.

View details for DOI 10.3389/fimmu.2025.1584916

View details for PubMedID 40534856

View details for PubMedCentralID PMC12173932

Abstract

Chronic immunosuppressive therapies are crucial in organ transplantation but can increase the risk of opportunistic infections and cancer over time. We investigated immune status changes in 10 kidney transplant patients and 11 age-matched healthy adults using broad in vitro stimulation of subject-derived peripheral blood mononuclear cells followed by mass cytometry by time of flight over 6 mo. Overall, the immune cells of transplant patients exhibited increased CD8+ T cell activation and differentiation compared with healthy donors, with elevated CD8+ CD57+, MIP-1β, and interferon γ production (P < 0.05, P < 0.05, and P < 0.01, respectively). CD107a and granzyme B expression were increased in CD8+ T cells and CD56bright natural killer cells (P < 0.05 and P < 0.01, respectively), while T regulatory cells had decreased interleukin-10 production (P < 0.05). These changes indicated a proinflammatory environment influenced by induction therapy and ongoing maintenance drugs. Additionally, transplant recipients displayed signs of immune modulation, including decreased tumor necrosis factor α, interferon γ, and MIP-1β expression in γδT cells (P < 0.05 and P < 0.01), and reduced interleukin-17 and granulocyte-macrophage colony-stimulating factor expression in CD8+ T memory cell subsets (P < 0.05). The diverse functional changes underscore the importance of comprehensive immune status profiling for optimizing individual treatment strategies and developing better immunosuppressants that specifically target activated cell populations.

View details for DOI 10.1093/immhor/vlae013

View details for PubMedID 39965168

Abstract

Liver ischemia-reperfusion injury (LIRI) profoundly affects liver function and survival largely through activation of the innate immune system. In this study we sought to elucidate the underlying mechanisms by which the innate immune system impacts liver function and survival in LIRI.RNA-seq analyses, from existing datasets of liver from mice with LIRI, was performed to identify differentially expressed genes (DEGs) associated with LIRI. Protein-protein interaction analysis revealed clusters involved in signaling pathways with a cluster anchored by Senp2, acting as a central modulator. Macrophages and monocytes were determined to be the source of Senp2 with monocyte-derived macrophages expressing the highest levels of Senp2. Experiments in a mouse model of LIRI further elucidated the expression, function, and mechanism of Senp2. Overexpression of Senp2 suppressed both the polarization of M1 macrophages and the production of inflammatory mediators. Further, Senp2-overexpressing macrophages significantly ameliorated LIRI.Our study suggests that SENP2 plays an important role in regulating LIRI by influencing macrophage polarization through the Dvl2/GSK-3β/β-catenin axis. While further validation is needed, these findings indicate that targeting SENP2-mediated pathways could be a promising approach for mitigating LIRI and enhancing therapeutic strategies.

View details for DOI 10.1016/j.biocel.2025.106741

View details for PubMedID 39890015

Abstract

The oncogenic Epstein-Barr virus (EBV) can drive tumorigenesis with disrupted host immunity, causing malignancies including post-transplant lymphoproliferative disorders (PTLDs). PTLD can also arise in the absence of EBV, but the biological differences underlying EBV(+) and EBV(-) B cell PTLD and the associated host-EBV-tumor interactions remain poorly understood. Here, we reveal the core differences between EBV(+) and EBV(-) PTLD, characterized by increased expression of genes related to immune processes or DNA interactions, respectively, and the augmented ability of EBV(+) PTLD B cells to modulate the tumor microenvironment through elaboration of monocyte-attracting cytokines/chemokines. We create a reference resource of proteins distinguishing EBV(+) B lymphoma cells from EBV(-) B lymphoma including the immunomodulatory molecules CD300a and CD24, respectively. Moreover, we show that CD300a is essential for maximal survival of EBV(+) PTLD B lymphoma cells. Our comprehensive multi-modal analyses uncover the biological underpinnings of PTLD and offer opportunities for precision therapies.

View details for DOI 10.1016/j.xcrm.2024.101851

View details for PubMedID 39657667

Abstract

Natural killer (NK) cells have gained recognition for playing an integral role in both alloimmunity and protective immunity, particularly viral infection control, in solid organ transplantation. Using data from the Clinical Trials in Organ Transplantation in Children (CTOTC) study entitled, "Immune Development in Pediatric Transplantation," (NCT00951353), we aimed to identify NK cell phenotypes that were associated with viral infection versus alloreactive events during the first year after transplantation. We also examined the relationship between NK cells with 7-year patient and allograft survival using the Scientific Registry for Transplant Recipients (SRTR) database.A secondary analysis of peripheral blood mononuclear cells from 98 children aged 1-20 years old with kidney transplants was conducted using multiparameter flow cytometry for the following NK cell phenotypes: CD56bright, CD56dim, and CD56negative. We associated these phenotypes with either viral infection or alloimmunity (de novo donor-specific antibody (dnDSA) development or acute rejection), using Fine-Gray subdistribution hazard models for competing risks. Secondary outcomes included allograft and patient survival.We demonstrated that specific baseline NK cell phenotypes obtained prior to transplantation may be associated with either viral infection or alloimmunity. An elevation in CD56dim frequency was associated with an increased risk of infection, while an increase in CD56negative absolute count was associated with an increased risk of an alloimmune event. NK cells were not associated with graft survival.NK cell phenotyping may be a useful tool to help differentiate infectious from alloimmune risk.

View details for DOI 10.1111/petr.14877

View details for PubMedID 39508125