Mathematical Modeling of Early Cellular Innate and Adaptive Immune Responses to Ischemia/Reperfusion Injury and Solid Organ Allotransplantation

SUMMARYDiverse effects of the microbiome on solid organ transplantation are beginning to be recognized. In allograft recipients, microbial networks are disrupted by immunosuppression, nosocomial and community-based infectious exposures, antimicrobial therapies, surgery, and immune processes. Shifting microbial patterns, including acute infectious exposures, have dynamic and reciprocal interactions with local and systemic immune systems. Both individual microbial species and microbial networks have central roles in the induction and control of innate and adaptive immune responses, in graft rejection, and in ischemia-reperfusion injury. Understanding the diverse interactions between the microbiome and the immune system of allograft recipients may facilitate clinical management in the future.

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Dual and Opposite Costimulatory Targeting with a Novel Human Fusion Recombinant Protein Effectively Prevents Renal Warm Ischemia Reperfusion Injury and Allograft Rejection in Murine Models

International Journal of Molecular Sciences ◽

10.3390/ijms22031216 ◽

2021 ◽

Vol 22 (3) ◽

pp. 1216

Author(s):

Jordi Guiteras ◽

Laura De Ramon ◽

Elena Crespo ◽

Nuria Bolaños ◽

Silvia Barcelo-Batllori ◽

...

Keyword(s):

Surface Plasmon Resonance ◽

Recombinant Protein ◽

Reperfusion Injury ◽

Surface Plasmon ◽

Plasmon Resonance ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Warm Ischemia ◽

Solid Organ ◽

Inflammatory Models

Many studies have shown both the CD28—D80/86 costimulatory pathway and the PD-1—PD-L1/L2 coinhibitory pathway to be important signals in modulating or decreasing the inflammatory profile in ischemia-reperfusion injury (IRI) or in a solid organ transplant setting. The importance of these two opposing pathways and their potential synergistic effect led our group to design a human fusion recombinant protein with CTLA4 and PD-L2 domains named HYBRI. The objective of our study was to determine the HYBRI binding to the postulated ligands of CTLA4 (CD80) and PD-L2 (PD-1) using the Surface Plasmon Resonance technique and to evaluate the in vivo HYBRI effects on two representative kidney inflammatory models—rat renal IRI and allogeneic kidney transplant. The Surface Plasmon Resonance assay demonstrated the avidity and binding of HYBRI to its targets. HYBRI treatment in the models exerted a high functional and morphological improvement. HYBRI produced a significant amelioration of renal function on day one and two after bilateral warm ischemia and on days seven and nine after transplant, clearly prolonging the animal survival in a life-sustaining renal allograft model. In both models, a significant reduction in histological damage and CD3 and CD68 infiltrating cells was observed. HYBRI decreased the circulating inflammatory cytokines and enriched the FoxP3 peripheral circulating, apart from reducing renal inflammation. In conclusion, the dual and opposite costimulatory targeting with that novel protein offers a good microenvironment profile to protect the ischemic process in the kidney and to prevent the kidney rejection, increasing the animal’s chances of survival. HYBRI largely prevents the progression of inflammation in these rat models.

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Ag-specific CD4 T cells promote innate immune responses in liver ischemia reperfusion injury

Cellular and Molecular Immunology ◽

10.1038/s41423-018-0051-x ◽

2018 ◽

Vol 16 (1) ◽

pp. 98-100 ◽

Cited By ~ 3

Author(s):

Jianhua Rao ◽

Feng Cheng ◽

Shikun Yang ◽

Yuan Zhai ◽

Ling Lu

Keyword(s):

T Cells ◽

Immune Responses ◽

Reperfusion Injury ◽

Cd4 T Cells ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Innate Immune ◽

Liver Ischemia ◽

Innate Immune Responses

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Two-Photon Imaging of Immune Cell Dynamics: Moving from 2D Fixed Tissue Sections to 3D Dynamic Histology In Vivo

Blood ◽

10.1182/blood.v122.21.sci-24.sci-24 ◽

2013 ◽

Vol 122 (21) ◽

pp. SCI-24-SCI-24

Author(s):

Mark J. Miller

Keyword(s):

Immune Responses ◽

Bacterial Infection ◽

Reperfusion Injury ◽

Immune Cell ◽

Ischemia Reperfusion Injury ◽

Inflammatory Diseases ◽

Ischemia Reperfusion ◽

Neutrophil Recruitment ◽

Neutrophil Extravasation

Abstract Cell-mediated immune responses are highly dependent on environmental context, thus making in vivo studies an important complement to in vitro and molecular approaches. Two-photon microscopy (2PM) is a fluorescence based imaging approach that allows single-cell dynamics to be studied directly in their 3D native tissue context. 2PM is an ideal approach for analyzing leukocyte trafficking dynamics quantitatively and testing cellular immune mechanisms in vivo. Several example applications will be presented where 2PM has uncovered novel immunological phenomena and provided fresh insight into immune responses to infection, autoimmunity and cancer. While 2P imaging has been used extensively to study immune cell trafficking and function in mice, progress is being made to use this imaging technique on clinical biopsy specimens to acquire a multi-dimensional picture of human tissue pathology. We used in vivo 2PM in pre-clinical models of arthritis and bacterial infection to compare and contrast the role of monocytes on neutrophil recruitment. The rapid recruitment of neutrophils and monocytes is critical to early host immune responses to bacterial infection. However, leukocyte recruitment also contributes to chronic inflammatory diseases such as human rheumatoid arthritis. Understanding how cell recruitment is regulated in different inflammatory contexts is crucial for developing safe and effective anti-inflammatory therapies. We found that monocyte depletion with clodronate-liposomes prevented arthritis development in a modified K/BxN serum transfer arthritis model. This protective effect was associated with significantly reduced neutrophil transendothelial migration efficiency. Furthermore, single-cell tracking of a minor population of extravasated neutrophils showed that neutrophil migration and chemotaxis in interstitial tissues was disrupted, contributing to decreased cell localization at phalangeal joints. Similar results were obtained when CCR2+ monocytes were depleted selectively using the monoclonal antibody MC-21, thus implicating CCR2+ monocytes as key regulators of neutrophil extravasation during arthritis initiation. In contrast, neutrophil recruitment to subcutaneous bacterial challenge remained intact and neutrophil extravasation and chemotaxis to sites of infection was not significantly different as compared to non-depleted controls. We also examined whether neutrophil extravasation during acute pulmonary inflammation required monocytes. Neutrophil recruitment in vivo was assessed in a mouse lung transplant-mediated ischemia reperfusion injury model. Similar to the results in the arthritis model, neutrophil recruitment in response to ischemia reperfusion injury was also monocyte dependent. In addition, Ccr2 knockout recipient mice were protected for ischemia reperfusion injury. Results from these complementary mouse models implicate CCR2+ monocytes as key regulators of neutrophil extravasation and chemotaxis in under conditions of aseptic inflammation and further suggest that the cell recruitment signals that that operate during bacterial infection may be quantitatively and/or qualitatively distinct. These studies raise the intriguing possibility that targeting monocytes during chronic inflammatory diseases such as rheumatoid arthritis or acute inflammatory conditions such as ischemia reperfusion injury might provide safer and more selective anti-inflammatory therapies than those that target neutrophils directly. Disclosures: No relevant conflicts of interest to declare.

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Cardiomyocyte-specific Bcl-2 overexpression attenuates ischemia-reperfusion injury, immune response during acute rejection, and graft coronary artery disease

Blood ◽

10.1182/blood-2004-02-0666 ◽

2004 ◽

Vol 104 (12) ◽

pp. 3789-3796 ◽

Cited By ~ 42

Author(s):

Masashi Tanaka ◽

Susumu Nakae ◽

Raya D. Terry ◽

Golnaz K. Mokhtari ◽

Feny Gunawan ◽

...

Keyword(s):

Coronary Artery Disease ◽

Coronary Artery ◽

Acute Rejection ◽

Immune Responses ◽

Reperfusion Injury ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Cardiac Allografts ◽

Artery Disease

After cardiac transplantation, graft damage occurs secondary to ischemia-reperfusion injury and acute rejection. This damage ultimately leads to the development of graft coronary artery disease (GCAD), which limits long-term graft survival. Apoptosis is directly involved in graft injury, contributing to the development of GCAD. To assess the role of the antiapoptotic factor Bcl-2 in the process of GCAD, we transplanted hearts from FVB transgenic mice overexpressing human Bcl-2 under the control of α-myosin heavy chain promoter into allogenic C57BL/6 mice. Bcl-2 overexpression led to reduced cytochrome c–mediated caspase-9–dependent cardiomyocyte apoptosis and local inflammation (neutrophil infiltration and proinflammatory cytokine production) in cardiac allografts during ischemia-reperfusion injury and also led to reduced immune responses (inflammatory cell infiltration, production of TH1 cytokines and chemokines, and expression of adhesion molecules) during acute and chronic rejection without affecting host CD4+ and CD8+ cell responses in the spleen. Thus, local Bcl-2 expression directly contributes to the modulation of local immune responses in allograft rejection, resulting in attenuated GCAD. In conclusion, our findings suggest that the modulation of Bcl-2 expression by pharmacologic up-regulation or gene transfer may be of clinical benefit in the short- and long-term function of cardiac allografts.

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Longitudinal immune profiling of a SARS-CoV-2 reinfection in a solid organ transplant recipient

10.1101/2021.03.24.21253992 ◽

2021 ◽

Author(s):

Jonathan Klein ◽

Anderson F. Brito ◽

Paul Trubin ◽

Peiwen Lu ◽

Patrick Wong ◽

...

Keyword(s):

Transplant Recipient ◽

Immune Responses ◽

Neutralizing Antibodies ◽

Primary Infection ◽

Organ Transplant Recipient ◽

Solid Organ Transplant Recipient ◽

Solid Organ ◽

Adaptive Immune Responses ◽

Adaptive Immune ◽

Immunological Mechanisms

Prior to the emergence of antigenically distinct SARS-CoV-2 variants, reinfections were reported infrequently - presumably due to the generation of durable and protective immune responses. However, case reports also suggested that rare, repeated infections may occur as soon as 48 days following initial disease onset. The underlying immunologic deficiencies enabling SARS-CoV-2 reinfections are currently unknown. Here we describe a renal transplant recipient who developed recurrent, symptomatic SARS-CoV-2 infection - confirmed by whole virus genome sequencing - 7 months after primary infection. To elucidate the immunological mechanisms responsible for SARS-CoV-2 reinfection, we performed longitudinal profiling of cellular and humoral responses during both primary and recurrent SARS-CoV-2 infection. We found that the patient responded to the primary infection with transient, poor-quality adaptive immune responses. The patients immune system was further compromised by intervening treatment for acute rejection of the renal allograft prior to reinfection. Importantly, we also identified the development of neutralizing antibodies and the formation of humoral memory responses prior to SARS-CoV-2 reinfection. However, these neutralizing antibodies failed to confer protection against reinfection, suggesting that additional factors are required for efficient prevention of SARS-CoV-2 reinfection. Further, we found no evidence supporting viral evasion of primary adaptive immune responses, suggesting that susceptibility to reinfection may be determined by host factors rather than pathogen adaptation in this patient. In summary, our study suggests that a low neutralizing antibody presence alone is not sufficient to confer resistance against reinfection. Thus, patients with solid organ transplantation, or patients who are otherwise immunosuppressed, who recover from infection with SARS-CoV-2 may not develop sufficient protective immunity and are at risk of reinfection.

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