Working toward immune tolerance in lung transplantation

Jiang, Xinguo; Nicolls, Mark R.

doi:10.1172/jci74701

Cited by 9 publications

(8 citation statements)

References 38 publications

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“…In this study, only 6% of the heart transplant recipients produced dnDSA, whereas 36% of lung transplant recipients produced dnDSA and both heart lung transplant recipients produced dnDSA. This supports the idea that the immunogenicity of lung transplantation is greater than heart transplantation due to the constant immune challenge associated with environmental exposure through respiration (Jiang & Nicolls, 2014). As the immunological risk of both heart and lung transplantation is currently assessed in the same way, both heart and lung transplant recipients were analysed together.…”

Section: Discussionmentioning

confidence: 55%

Human leukocyte antigen epitope mismatch loads and the development of de novo donor‐specific antibodies in cardiothoracic organ transplantation

Bedford

Jervis

Worthington

et al. 2021

Int J Immunogenetics

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De novo donor-specific human leucocyte antigen (HLA) antibodies (dnDSA) are associated with increased risk of rejection and mortality in solid organ transplantation. Such dnDSA is produced in some recipients upon allorecognition of mismatched HLA posttransplant. HLA matching is not currently considered in the allocation of deceased donor hearts and lungs and pre-transplant immunological risk stratification is based entirely on the mean fluorescence intensity (MFI) of circulating donor-directed HLA antibodies. HLA epitope-based matching tools predict B-cell or T-cell HLA epitopes that are present in the donor's HLA but absent in the recipient's HLA. We hypothesized that patients with higher epitope mismatch loads would be at increased risk of dnDSA development. We retrospectively analysed 73 heart and/or lung transplant recipients who were tested for DSA between 2015 and 2020. HLAMatchmaker, PIRCHE-II and HLA epitope mismatch algorithm (HLA-EMMA) were used to calculate eplet mismatch (EpMM) loads, T-cell epitope mismatch (TEpMM) loads and solvent accessible amino acid mismatch (SAMM) loads, respectively. Multivariate analyses showed that HLA-EMMA was the only tool with a significant association between the total score for all HLA loci and dnDSA production [odds ratio (OR) 1.021, 95% confidence interval (CI) 1.003-1.042, p = .0225] though this increased risk was marginal. The majority of dnDSA were directed against HLA-DQ and patients with higher HLA-DQ TEpMM loads (OR = 1.008, CI = 1.002-1.014, p = .007), and HLA-DR+DQ SAMM loads (OR = 1.035, CI = 1.010-1.064, p = .0077) were most at risk of producing dnDSA.We also showed that patients with a risk epitope within the HLA molecule encoded for by HLA-DQA1*05 + HLA-DQB1*02/03:01 were significantly more likely to produce dnDSA. The use of HLA epitope-based matching tools could be used for cardiothoracic transplant risk stratification to enable early intervention and monitoring of patients at increased risk of producing dnDSA.

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Section: Discussionmentioning

confidence: 55%

Human leukocyte antigen epitope mismatch loads and the development of de novo donor‐specific antibodies in cardiothoracic organ transplantation

Bedford

Jervis

Worthington

et al. 2021

Int J Immunogenetics

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“…MEK inhibition may also suppress graft rejection after solid organ transplantation; however, several topics should be investigated. In contrast with bone marrow transplantation, host immunity is not ablated and immunological tolerance is unlikely after lung transplantation (19). The thymus is not ablated, and it is unknown how MEK inhibition modulates thymic function upon solid organ transplantation.…”

mentioning

confidence: 99%

Trametinib Attenuates Delayed Rejection and Preserves Thymic Function in Rat Lung Transplantation

Takahagi¹,

Shindo

Chen‐Yoshikawa³

et al. 2019

Am J Respir Cell Mol Biol

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Delayed immunological rejection after human lung transplantation causes chronic lung allograft dysfunction, which is associated with high mortality. Delayed rejection may be attributable to indirect alloantigen presentation by host antigen-presenting cells; however, its pathophysiology is not fully understood. The mitogen-activated protein kinase pathway is activated in T cells upon stimulation, and we previously showed that the MEK inhibitor, trametinib, suppresses graft-versus-host disease after murine bone marrow transplantation. We investigated whether trametinib suppresses graft rejection after two types of rat lung transplantation and analyzed its immunological mode of action. Major histocompatibility complex-mismatched transplantation from brown Norway rats into Lewis rats and minor histocompatibility antigen-mismatched transplantation from Fischer 344 rats into Lewis rats were performed. Cyclosporine (CsA) and/or trametinib were administered alone or consecutively. Acute and delayed rejection, lymphocyte infiltration, and pulmonary function were evaluated. Administration of trametinib after CsA suppressed delayed rejection, reduced inflammatory cell infiltration and fibrosis within the graft, and preserved pulmonary functions at Day 28. Trametinib suppressed functional differentiation of T and B cells in the periphery but preserved thymic T cell differentiation. Donor B cells within the graft disappeared by Day 14, indicating that delayed graft rejection at Day 28 was mainly due to indirect presentation by host antigen-presenting cells. Finally, trametinib administration without CsA preconditioning suppressed rejection after minor histocompatibility antigen-mismatched transplantation. Trametinib attenuates delayed rejection upon major histocompatibility complex-mismatched transplantation by suppressing indirect presentation and is a promising candidate to treat chronic lung allograft dysfunction in humans.

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“…They are either those of neonates or that of mature conventional and / or transgenic [19]. Like murine model for lung transplantation [20], and human CD3 trasngenic mice [21]. The present lapin model of oral mucosal tolerance, mucosal application of S. typhi bacterin induce low specific agglutination, specific IgM, Specific IgG as well as a mild rate of class switching from IgM to IgG.…”

Section: Resultsmentioning

confidence: 99%

Oral Mucosal Tolerance Versus Systemic Immune Response to Salmonella typhi Antigen

Shnawa¹

2015

AJBLS

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It was demonstrated that the oral vaccine application of Salmonella typhi antigen can activate low antibody agglutinin titer (mean:40±0) comparing with high agglutination titer induced by Intramuscular administration of Salmonella typhi antigen (mean 560.0 ± 51.64) as well as anti-Salmonella typhi IgG ELIZA shows high mean index value(mean = 0.6957±0.10) comparing with the low index value induced by oral rout were (mean= 0.028±0.014) while anti Salmonella typhi IgM ELIZA test show mean index value = 0.6339±0.0385 comparing with low IgM index value (mean= 0.1560±0.070) induced by oral rout (Rsquared 0.7457, t test 3.3. The pro-inflammatory cytokines IL-1α was high in intramuscular rout 217.089±39.78 than its concentration with in oral administrated group (100.4±12.09), IL-12 was about the same concentration both in oral rout and intramuscular rout subsequently (23.607 and 23.17) p value 0.01, R squared (0.3958).However the immune responses were not absolutely absent in the oral administrated group, this reflect the fact that there is a selectivity in taking oral antigens from digestive mucosal surfaces but this immune feature and selectivity theme may vary from antigen to another. In conclusion the recent and ongoing expansion of a new information about the mucosal and systemic immune responses lend a promise to provide the tools needed to exploit the full potential and development of both mucosal and intramuscular vaccines.

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Working toward immune tolerance in lung transplantation

Cited by 9 publications

References 38 publications

Human leukocyte antigen epitope mismatch loads and the development of de novo donor‐specific antibodies in cardiothoracic organ transplantation

Human leukocyte antigen epitope mismatch loads and the development of de novo donor‐specific antibodies in cardiothoracic organ transplantation

Trametinib Attenuates Delayed Rejection and Preserves Thymic Function in Rat Lung Transplantation

Oral Mucosal Tolerance Versus Systemic Immune Response to Salmonella typhi Antigen

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