scholarly journals Suppression of liver transplant rejection by anti-donor MHC antibodies via□ depletion of donor immunogenic dendritic cells

2020 ◽  
Author(s):  
Hisashi Ueta ◽  
Xue-Dong Xu ◽  
Bin Yu ◽  
Yusuke Kitazawa ◽  
Enqiao Yu ◽  
...  
Keyword(s):  
T Cell ◽  
Liver Transplant ◽  
Transplant Rejection ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Cellular Damage ◽  
Class I Mhc ◽  
Class Ii Mhc ◽  
Passenger Leukocytes ◽  
Liver Transplant Rejection

Abstract Background We previously found two distinct passenger dendritic cell (DC) subsets in the rat liver that played a central role in the liver transplant rejection. In addition, tolerance-inducing protocol, donor-specific transfusion (DST), triggered systemic polytopical production of depleting alloantibodies to donor class I MHC antigen (DST-antibodies). Methods We examined the role of DST-antibodies in the trafficking of graft DC subsets and the alloresponses in a rat model. We also examined an anti-donor class II MHC (MHCII) antibody that recognizes donor DCs more selectively. Results Preoperative transfer of DST-antibodies and DST pretreatments eliminated all passenger leukocytes, including both DC subsets and depleted the sessile DCs in the graft to ~20% of control. The CD172a +CD11b/c + immunogenic subset was almost abolished. The intrahost direct or semi-direct allorecognition pathway was successfully blocked, leading to a significant suppression of the CD8 + T-cell response in the recipient lymphoid organs and the graft with delayed graft rejection. Anti-donor MHCII antibody had similar effects without temporary graft damage. Although DST pretreatment had a priming effect on the recipient Treg proliferative response, DST-primed sera and the anti-donor MHCII antibody did not. Conclusion DST-antibodies and anti-donor MHCII antibodies could suppress the CD8 + T-cell-mediated liver transplant rejection by depleting donor immunogenic DCs, blocking the direct or semi-direct pathway of allorecognition. Donor MHCII-specific antibodies may be applicable as a selective suppressant of anti-donor immunity for clinical liver transplantation without the cellular damage of donor MHCII – graft cells and recipient cells.

scholarly journals S2680 Delayed T-cell Mediated Liver Transplant Rejection

2021 ◽  
Vol 116 (1) ◽  
pp. S1124-S1124
Author(s):  
Matthew Everwine ◽  
David Truscello ◽  
Sindhu Maramupdi ◽  
Valentina Del Signore ◽  
Sangam Shivaprasad ◽  
...  
Keyword(s):  
T Cell ◽  
Liver Transplant ◽  
Transplant Rejection ◽  
Liver Transplant Rejection

169 Microfluidics cell squeezing enables human PBMCs as drivers of antigen-specific CD8 T responses across broad range of antigens for diverse clinical applications

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A183-A183
Author(s):  
Michael Maloney ◽  
Scott Loughhead ◽  
Amritha Ramakrishnan ◽  
Carolyne Smith ◽  
Anita Venkitaraman ◽  
...  
Keyword(s):  
T Cell ◽  
Mononuclear Cells ◽  
Scale Up ◽  
Cell Activity ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Human Pbmcs ◽  
Class I Mhc ◽  
Wide Range ◽  
The Impact

BackgroundAntigen-specific CD8+ T cell activity is critical for mounting an effective immune response in a wide range of indications, including immune-oncology and infectious diseases.MethodsTo elicit antigen-specific CD8+ T cell activity, we used microfluidics cell squeezing (Cell Squeeze®) to deliver antigens directly to the cytosol of antigen presenting cells (APCs). Direct cytosolic delivery bypasses the need for cross-presentation and efficiently loads antigen into the major histocompatibility complex class I (MHC-I) pathway. The Cell Squeeze® platform is generally agnostic to cell type and material. Therefore, not only does microfluidic squeezing enable cell subsets within human peripheral blood mononuclear cells (PBMCs) to function as unconventional APCs, but it also enables us to efficiently investigate a wide range of antigens including whole protein, peptides, and mRNA. This ‘plug and play’ nature of the platform allows for broad application in multiple disease areas.ResultsIn human cells, we demonstrated that microfluidic squeezing of PBMCs enables effective delivery to the major cell subsets including T cells, B cells, NK cells and monocytes. Delivery of CMV and HPV16 synthetic long peptides (SLPs) resulted in robust in vitro responses of both CD8+ T cell clones and patient-derived memory populations. To broaden the impact of our PBMC-based cell therapy approach, we investigated several other antigens relevant to other disease areas. Additional materials we delivered via squeezing and demonstrated antigen presentation include neoantigens, M1 Influenza mRNA, and pp65 SLP. Cell Squeeze® platform is simple to use and amenable to scale up. We demonstrated that delivery and viability for research scale process (~2 × 106 cells) is equivalent to delivery and viability of PBMCs processed at manufacturing scale (~1 × 109 cells).ConclusionsMicrofluidic cell squeezing of human PBMCs with antigenic material can be tailored to produce APCs that drive robust CD8+ T cell response against targets across multiple disease areas and has been scaled up for clinical use. SQZ-PBMC-HPV are currently under clinical evaluation for treatment of HPV16+ tumors.

ORGAN-SPECIFIC T-CELL GROWTH FACTOR AND CTL GENE ACTIVATION IN RENAL AND LIVER TRANSPLANT REJECTION

1999 ◽  
Vol 67 (7) ◽  
pp. S248 ◽  
Author(s):  
J Strehlau ◽  
B Nashan ◽  
C v Schnakenburg ◽  
G Demirci ◽  
A Strasburg ◽  
...  
Keyword(s):  
T Cell ◽  
Growth Factor ◽  
Cell Growth ◽  
Liver Transplant ◽  
Transplant Rejection ◽  
Gene Activation ◽  
Organ Specific ◽  
Liver Transplant Rejection ◽  
T Cell Growth ◽  
T Cell Growth Factor

Polyfunctional CD8+ T-Cell Response to Autologous Peptides from Protease and Reverse Transcriptase of HIV-1 Clade B

2019 ◽  
Vol 17 (5) ◽  
pp. 350-359
Author(s):  
Liliana Acevedo-Saenz ◽  
Federico Perdomo-Celis ◽  
Carlos J. Montoya ◽  
Paula A. Velilla
Keyword(s):  
T Cell ◽  
Reverse Transcriptase ◽  
Cellular Response ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Effective Vaccine ◽  
Cell Responses ◽  
Clade B ◽  
Hiv 1

Background: : The diversity of the HIV proteome influences the cellular response and development of an effective vaccine, particularly due to the generation of viral variants with mutations located within CD8+ T-cell epitopes. These mutations can affect the recognition of the epitopes, that may result in the selection of HIV variants with mutated epitopes (autologous epitopes) and different CD8+ T-cell functional profiles. Objective:: To determine the phenotype and functionality of CD8+ T-cell from HIV-infected Colombian patients in response to autologous and consensus peptides derived from HIV-1 clade B protease and reverse transcriptase (RT). Methods:: By flow cytometry, we compared the ex vivo CD8+ T-cell responses from HIV-infected patients to autologous and consensus peptides derived from HIV-1 clade B protease and RT, restricted by HLA-B*35, HLA-B*44 and HLA-B*51 alleles. Results:: Although autologous peptides restricted by HLA-B*35 and HLA-B*44 did not show any differences compared with consensus peptides, we observed the induction of a higher polyfunctional profile of CD8+ T-cells by autologous peptides restricted by HLA-B*51, particularly by the production of interferon-γ and macrophage inflammatory protein-1β. The response by different memory CD8+ T-cell populations was comparable between autologous vs. consensus peptides. In addition, the magnitude of the polyfunctional response induced by the HLA-B*51-restricted QRPLVTIRI autologous epitope correlated with low viremia. Conclusion:: Autologous peptides should be considered for the evaluation of HIV-specific CD8+ Tcell responses and to reveal some relevant epitopes that could be useful for therapeutic strategies aiming to promote polyfunctional CD8+ T-cell responses in a specific population of HIV-infected patients.

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