Tolerance and Immunity following in Utero Transplantation of Allogeneic Fetal Liver Cells: The Cytokine Shift

2003 ◽  
Vol 12 (1) ◽  
pp. 75-82 ◽  
Author(s):  
H. Sefrioui, J. Donahue ◽  
E. A. Gilpin ◽  
A. S. Srivastava ◽  
E. Carrier
Keyword(s):  
T Cells ◽  
Fetal Liver ◽  
Solid Organ Transplantation ◽  
Tolerance Induction ◽  
Suppressor Cells ◽  
In Utero ◽  
Third Party ◽  
Solid Organ ◽  
In Utero Transplantation ◽  
Ifn Γ

Although in utero transplantation (IUT) has resulted in donor-specific tolerance to postnatal solid organ transplantation, the mechanisms of this tolerance remain poorly understood. Our recent findings demonstrate that under specific conditions prenatal injection of allogeneic cells may lead to allosensitization instead of tolerance. These laboratory observations were supported by clinical findings as well, and therefore suggested that, depending on the conditions of prenatal transplantation, tolerance or immunity may develop. The present study explored the role of CD4 cells, cytokines, and I-E superantigen in developing tolerance vs. immunity after in utero transplantation. Sixteen animals survived IUT (40–60% survival rate) and were free from any signs of graft-versus-host disease (GVHD). Mice were considered tolerant when their antidonor and antihost CTL responses were similar, sensitized when antidonor responses were significantly higher than antihost and anti-third-party responses, and nontolerant when antidonor responses in transplanted and control mice were similar. The TH1 → TH2 shift was associated with tolerance and TH2 → TH1 shift with allosensitization. Our results showed that tolerant BALB/c (H-2d, I-E+) → C57BL/6 (H-2b, I-E–) (2/7) mice showed higher IL-4 (p < 0.05) in antidonor MLR, and partial deletion of recipient I-E-reactive T cells (CD3Vβ11) (p < 0.045). On the other hand, nontolerant animals (5/7) demonstrated high production of IFN-γ (p < 0.05) without deletion of CD3Vβ11 T cells. In C57CBL/6 (H-2b, I-E–) → C3H (H-2k, I-E+) mice CD3Vβ11 T cells do not play any role in tolerance induction because they are deleted in the C3H background. Tolerant mice (4/9) showed an overproduction of IL-4 (p < 0.05) in antidonor MLR whereas allosensitized animals (5/9) demonstrated high level of IFN-γ (p < 0.05). Suppressor cells seem to play no role in tolerant C57BL/6 → C3H as demonstrated by suppressor assay. Hence, a shift from TH1 → TH2 or TH2 → TH1 cytokines may determine whether tolerance or immunity develops.

scholarly journals Regulatory T cells: tolerance induction in solid organ transplantation

2017 ◽  
Vol 189 (2) ◽  
pp. 197-210 ◽  
Author(s):  
T. Vaikunthanathan ◽  
N. Safinia ◽  
D. Boardman ◽  
R. I. Lechler ◽  
G. Lombardi
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Organ Transplantation ◽  
Solid Organ Transplantation ◽  
Tolerance Induction ◽  
Solid Organ

scholarly journals Oridonin Prolongs the Survival of Mouse Cardiac Allografts by Attenuating the NF-κB/NLRP3 Pathway

2021 ◽  
Vol 12 ◽  
Author(s):  
Xiaoxiao Du ◽  
Weitao Que ◽  
Xin Hu ◽  
Xiao Yu ◽  
Wen-Zhi Guo ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Organ Transplantation ◽  
Mrna Level ◽  
Solid Organ Transplantation ◽  
Solid Organ ◽  
Transplant Tolerance ◽  
Term Survival ◽  
Cardiac Allografts ◽  
Ifn Γ

BackgroundOridonin (Ori), the main bioactive ingredient of the natural anti-inflammatory herb Rabdosia rubescens, could be a covalent inhibitor of the NLRP3 inflammasome. Solid organ transplantation provides a life-saving optional therapy for patients with end-stage organ dysfunction. The long-term survival of solid organ transplantation remains restricted because of the possibility of rejection and the toxicity, infection, cardiovascular disease, and malignancy related to immunosuppressive (IS) drugs. However, the pathogenic mechanisms involved remain unclear. The ideal IS drugs to prevent allograft rejection have not been identified. Here, we investigated whether Ori could prolong the in vivo survival of completely mismatched cardiac allografts.MethodsThe cardiac transplantation models were conducted among three groups of mice from C57BL/6NCrSlc (B6/N) or C3H/HeNSlc (C3H) to C3H: the syngeneic and the allogeneic group, whose recipients were treated with vehicle of Ori, and the Ori treatment group, in which the recipients were transplanted hearts from MHC-I mismatched donors and treated with different dosages of Ori from post-operative day (POD) 0 to 7. Then, we investigated the effect of Ori on bone marrow-derived dendritic cell (BMDC) and allogeneic mixed lymphocyte reaction in vitro.ResultsOri with 3, 10, and 15 mg/kg Ori could prolong the survival (MST = 22.8, 49.2, and 65.3 days, respectively). We found that infiltrating CD8+ T cells and macrophages were decreased, and regulatory T cells (Tregs) were expanded in allografts on POD7. The mRNA level of IL-1β and IFN-γ of allografts was downregulated. Mechanistically, Ori-treated BMDCs suppressed T-cell proliferation and IFN-γ+CD4+ T-cell differentiation, along with the expansion of Tregs and IL-10+CD4+ T cells. Ori inhibited NOD, LRR-, and pyrin domain-containing protein 3 (NLRP3) expression; attenuated NF-κB and IκBα phosphorylation in LPS-activated BMDCs; downregulated NLRP3, Caspase-1, IL-1β, IL-18, and IFN-γ; and upregulated IL-10 expression.ConclusionsOur findings highlight the potential of Ori as a novel and natural IS agent to improve transplant tolerance. Ori could exert IS activity through decreasing IL-1β and IL-18 production and Th1 differentiation and proliferation and expanding Tregs via inhibiting the NF-κB/NLRP3 signaling pathway.

Tolerance induction of alloreactive T cells via ex vivo blockade of the CD40:CD40L costimulatory pathway results in the generation of a potent immune regulatory cell

Blood ◽  
2002 ◽  
Vol 99 (12) ◽  
pp. 4601-4609 ◽  
Author(s):  
Patricia A. Taylor ◽  
Thea M. Friedman ◽  
Robert Korngold ◽  
Randolph J. Noelle ◽  
Bruce R. Blazar
Keyword(s):  
T Cells ◽  
Ex Vivo ◽  
Solid Organ Transplantation ◽  
Tolerance Induction ◽  
Regulatory Function ◽  
Solid Organ ◽  
Regulatory Cell ◽  
Costimulatory Blockade ◽  
Alloreactive T Cells ◽  
Costimulatory Pathway

We previously reported that ex vivo blockade of the CD40:CD40L costimulatory pathway in primary mixed lymphocyte reaction cultures resulted in profound in vitro secondary hyporesponsiveness and 30-fold or greater protection from graft-versus-host-disease (GVHD) lethality. Present studies demonstrate that tolerance induction via costimulatory blockade also results in the generation of a potent immunoregulatory cell that inhibits both naive and primed alloresponses. The immunoregulatory capacity was dependent upon cell-to-cell contact that prevented the full activation of the naive or primed cells. The inhibitory effect of tolerized cells did not preclude the response of naive T cells to nominal protein antigen if antigen was present at high concentration. However, under suboptimal antigen concentration, nonspecific inhibition of responses occurred. The tolerized regulatory cell population maintained a polyclonal T-cell receptor Vβ repertoire that was broader than in control primed cultures. These data, the first to demonstrate that tolerance induction via CD40:CD40L costimulatory blockade results in potent regulatory function, are relevant to bone-marrow and solid-organ transplantation. The generation of potent immunoregulatory capacity during tolerization via CD40:CD40L blockade provides a fail-safe mechanism to control alloreactive T cells that may have escaped tolerization. These potent regulatory cells may be clinically exploitable for the treatment and prevention of GVHD or autoimmunity.

scholarly journals Cd4+Cd25+ Immune Regulatory Cells Are Required for Induction of Tolerance to Alloantigen via Costimulatory Blockade

2001 ◽  
Vol 193 (11) ◽  
pp. 1311-1318 ◽  
Author(s):  
Patricia A. Taylor ◽  
Randolph J. Noelle ◽  
Bruce R. Blazar
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cytotoxic T Lymphocyte ◽  
Ex Vivo ◽  
Solid Organ Transplantation ◽  
Tolerance Induction ◽  
Solid Organ ◽  
Induction Of Tolerance

Immune regulatory CD4+CD25+ cells play a vital role in the induction and maintenance of self-tolerance and are essential for T cell homeostasis and the prevention of autoimmunity. Induction of tolerance to allogeneic donor grafts is a clinically desirable goal in bone marrow and solid organ transplantation. To determine whether CD4+CD25+ cells regulate T cell responses to alloantigen and are critical for tolerance induction, murine CD4+ T cells were tolerized to alloantigen via ex vivo CD40 ligand (CD40L)/CD40 or CD28/cytotoxic T lymphocyte–associated antigen 4/B7 blockade resulting in secondary mixed leukocyte reaction hyporesponsiveness and tolerance to alloantigen in vivo. CD4+CD25+ T cells were found to be potent regulators of alloresponses. Depletion of CD4+CD25+ T cells from the CD4+ responder population completely abrogated ex vivo tolerance induction to alloantigen as measured by intact responses to alloantigen restimulation in vitro and in vivo. Addback of CD4+CD25+ T cells to CD4+CD25− cultures restored tolerance induction. These data are the first to indicate that CD4+CD25+ cells are essential for the induction of tolerance to alloantigen and have important implications for tolerance-inducing strategies targeted at T cell costimulatory pathways.

scholarly journals Comparison of Three Cellular Assays to Predict the Course of CMV Infection in Liver Transplant Recipients

Vaccines ◽  
2021 ◽  
Vol 9 (2) ◽  
pp. 88
Author(s):  
Smaranda Gliga ◽  
Melanie Fiedler ◽  
Theresa Dornieden ◽  
Anne Achterfeld ◽  
Andreas Paul ◽  
...  
Keyword(s):  
Liver Transplant ◽  
Solid Organ Transplantation ◽  
Solid Organ ◽  
Transplant Recipients ◽  
Cmv Infection ◽  
Cellular Assays ◽  
Risk Patients ◽  
Ifn Γ ◽  
Liver Transplant Recipients

To estimate protection from cytomegalovirus (CMV) replication after solid organ transplantation, CMV serology has been considered insufficient and thus CMV immunity is increasingly assessed by cellular in vitro methods. We compared two commercially available IFN-γ ELISpot assays (T-Track CMV and T-SPOT.CMV) and an IFN-γ ELISA (QuantiFERON-CMV). Currently, there is no study comparing these three assays. The assays were performed in 56 liver transplant recipients at the end of antiviral prophylaxis and one month thereafter. In CMV high- or intermediate-risk patients the two ELISpot assays showed significant correlation (p < 0.0001, r > 0.6) but the correlation of the ELISpot assays with QuantiFERON-CMV was weaker. Results of both ELISpot assays were similarly predictive of protection from CMV-DNAemia ≥500 copies/mL [CMV pp65 T-SPOT.CMV at the end of prophylaxis: area under curve (AUC) = 0.744, cut-off 142 spot forming units (SFU), sensitivity set to 100%, specificity 46%; CMV IE-1 T-Track CMV at month 1: AUC = 0.762, cut-off 3.5 SFU, sensitivity set to 100%, specificity 59%]. The QuantiFERON-CMV assay was inferior, reaching a specificity of 23% when setting the sensitivity to 100%. In conclusion, both CMV-specific ELISpot assays appear suitable to assess protection from CMV infection/reactivation in liver transplant recipients.

Low-dose of tacrolimus favors the induction of functional CD4+CD25+FoxP3+ regulatory T cells in solid-organ transplantation

2009 ◽  
Vol 9 (5) ◽  
pp. 564-569 ◽  
Author(s):  
Zhen Wang ◽  
Bingyi Shi ◽  
Hailong Jin ◽  
Li Xiao ◽  
Yongwei Chen ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Organ Transplantation ◽  
Low Dose ◽  
Solid Organ Transplantation ◽  
Solid Organ

scholarly journals Large Animal Models of Vascularized Composite Allotransplantation: A Review of Immune Strategies to Improve Allograft Outcomes

2021 ◽  
Vol 12 ◽  
Author(s):  
Abraham J. Matar ◽  
Rebecca L. Crepeau ◽  
Gerhard S. Mundinger ◽  
Curtis L. Cetrulo ◽  
Radbeh Torabi
Keyword(s):  
Animal Models ◽  
Ex Vivo ◽  
Solid Organ Transplantation ◽  
Tolerance Induction ◽  
Large Animal ◽  
Solid Organ ◽  
Large Animal Models ◽  
Large Animals ◽  
And Function ◽  
Made In

Over the past twenty years, significant technical strides have been made in the area of vascularized composite tissue allotransplantation (VCA). As in solid organ transplantation, the allogeneic immune response remains a significant barrier to long-term VCA survival and function. Strategies to overcome acute and chronic rejection, minimize immunosuppression and prolong VCA survival have important clinical implications. Historically, large animals have provided a valuable model for testing the clinical translatability of immune modulating approaches in transplantation, including tolerance induction, co-stimulation blockade, cellular therapies, and ex vivo perfusion. Recently, significant advancements have been made in these arenas utilizing large animal VCA models. In this comprehensive review, we highlight recent immune strategies undertaken to improve VCA outcomes with a focus on relevant preclinical large animal models.

scholarly journals The self-peptide repertoire plays a critical role in transplant tolerance induction

2020 ◽  
Author(s):  
Eric T. Son ◽  
Pouya Faridi ◽  
Moumita Paul-Heng ◽  
Mario Leong ◽  
Kieran English ◽  
...  
Keyword(s):  
T Cells ◽  
Critical Role ◽  
Tolerance Induction ◽  
Genetically Engineered ◽  
Solid Organ ◽  
Transplant Tolerance ◽  
Mhc I ◽  
Definitive Evidence ◽  
Antigen Presentation Pathway ◽  
Presentation Pathway

AbstractWhile direct allorecognition underpins both solid organ allograft rejection and tolerance induction, the specific molecular targets of most directly-alloreactive CD8+T cells have not been defined. In this study, we used a combination of genetically-engineered MHC I constructs, mice with a hepatocyte-specific mutation in the class I antigen-presentation pathway and immunopeptidomic analysis to provide definitive evidence for the contribution of the peptide cargo of allogeneic MHC I molecules to transplant tolerance induction. We established a systematic approach for the discovery of directly-recognised pMHC epitopes, and identified 17 strongly immunogenic H-2Kb-associated peptides recognised by CD8+T cells from B10.BR (H-2k) mice, 13 of which were also recognised by BALB/c (H-2d) mice. As few as five different tetramers used together were able to identify almost 40% of alloreactive T cells within a polyclonal population, suggesting that there are immunodominant allogeneic MHC-peptide complexes that can account for a large proportion of the alloresponse.

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