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iNKT and transplantation

Koji Kawaguchi, Katsutsugu Umeda, Eitaro Hiejima, Atsushi Iwai, Masamitsu Mikami, Seishiro Nodomi, Satoshi Saida, Itaru Kato, Hidefumi Hiramatsu, Takahiro Yasumi, Ryuta Nishikomori, Tadakazu Kondo, Akifumi Takaori-Kondo, Toshio Heike, Souichi Adachi
Mucosal-associated invariant T (MAIT) and invariant natural killer T (iNKT) cells are T cell subpopulations that possess innate-like properties. We examined the impact of post-hematopoietic stem cell transplantation (HSCT) MAIT and iNKT cell recovery on the clinical outcomes of 69 patients who underwent allogeneic HSCT at Kyoto University Hospital. Multivariate analyses identified the absolute number of MAIT cells (< 0.48/μL on day 60 post-HSCT) as the sole independent risk factor for grade I-IV and grade II-IV acute graft-versus-host disease (aGVHD) among patients who underwent bone marrow transplantation; no correlation was observed between post-HSCT iNKT cell recovery and the development of aGVHD...
March 26, 2018: International Journal of Hematology
Amy C Prosser, Axel Kallies, Michaela Lucas
Short-term outcomes of solid organ transplantation have improved dramatically over the past several decades; however, long-term survival has remained static over the same time period, and chronic rejection remains a major cause of graft failure. The importance of donor, or 'passenger', lymphocytes to the induction of tolerance to allografts was recognized in the 1990s; however, their precise contribution to graft acceptance or rejection has not been elucidated. Recently, specialized populations of tissue-resident lymphocytes in nonlymphoid organs have been described...
November 14, 2017: Transplantation
Rumi Ishii, Toshihito Hirai, Satoshi Miyairi, Kazuya Omoto, Masayoshi Okumi, Yasuyuki Ishii, Kazunari Tanabe
Transplant tolerance induction makes it possible to preserve functional grafts for a lifetime without immunosuppressants. One powerful method is to generate mixed hematopoietic chimeras in recipients by adoptive transfer of donor-derived bone marrow cells (BMCs). In our murine transplantation model, we established a novel method for mixed chimera generation using sublethal irradiation, CD40-CD40L blockade, and invariant natural killer T-cell activation. However, numerous BMCs that are required to achieve stable chimerism makes it difficult to apply this model for human transplantation...
August 2, 2017: American Journal of Transplantation
Shuyu E, Aman Seth, Peter Vogel, Matt Sommers, Taren Ong, Asha B Pillai
Nonmyeloablative conditioning using total lymphoid irradiation (TLI) and rabbit antithymocyte serum (ATS) (the murine preclinical equivalent of antithymocyte globulin [ATG]) facilitates immune tolerance after bone marrow transplantation (BMT) across major histocompatibility complex (MHC) disparities and may be a useful strategy for nonmalignant disorders. We previously reported that donor effector T-cell function and graft-versus-host disease (GVHD) are regulated via recipient invariant natural killer T-cell (iNKT) interleukin-4-driven expansion of donor Foxp3+ naturally occurring regulatory T cells (Tregs)...
June 1, 2017: Blood
Satoshi Miyairi, Toshihito Hirai, Rumi Ishii, Masayoshi Okumi, Shinichi Nunoda, Kenji Yamazaki, Yasuyuki Ishii, Kazunari Tanabe
Mixed chimerism induction is the most reliable method for establishing transplantation tolerance. We previously described a novel treatment using a suboptimal dose of anti-CD40 ligand (anti-CD40L) and liposomal formulation of a ligand for invariant natural killer T cells administered to sub-lethally irradiated recipient mice after donor bone marrow cell (BMC) transfer. Recipient mice treated with this regimen showed expansion of a Foxp3-positive regulatory T(Treg) cell phenotype, and formation of mixed chimera...
April 2017: European Journal of Immunology
David Hongo, Xiaobin Tang, Xiangyue Zhang, Edgar G Engleman, Samuel Strober
The combination of total lymphoid irradiation and anti-T-cell antibodies safely induces immune tolerance to combined hematopoietic cell and organ allografts in humans. Our mouse model required host natural killer T (NKT) cells to induce tolerance. Because NKT cells normally depend on signals from CD8+ dendritic cells (DCs) for their activation, we used the mouse model to test the hypothesis that, after lymphoid irradiation, host CD8+ DCs play a requisite role in tolerance induction through interactions with NKT cells...
March 23, 2017: Blood
Thirumahal Selvanantham, Qiaochu Lin, Cynthia Xinyi Guo, Anuradha Surendra, Stephanie Fieve, Nichole K Escalante, David S Guttman, Catherine J Streutker, Susan J Robertson, Dana J Philpott, Thierry Mallevaey
NKT cells are unconventional T cells that respond to self and microbe-derived lipid and glycolipid Ags presented by the CD1d molecule. Invariant NKT (iNKT) cells influence immune responses in numerous diseases. Although only a few studies have examined their role during intestinal inflammation, it appears that iNKT cells protect from Th1-mediated inflammation but exacerbate Th2-mediated inflammation. Studies using iNKT cell-deficient mice and chemically induced dextran sodium sulfate (DSS) colitis have led to inconsistent results...
December 1, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
M-T Rubio, M Bouillié, N Bouazza, T Coman, H Trebeden-Nègre, A Gomez, F Suarez, D Sibon, A Brignier, E Paubelle, S Nguyen-Khoc, M Cavazzana, O Lantz, M Mohty, S Urien, O Hermine
Clinically useful pre-transplant predictive factors of acute graft-versus-host-disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (allo-SCT) are lacking. We prospectively analyzed HSC graft content in CD34(+), NK, conventional T, regulatory T and invariant natural killer T (iNKT) cells in 117 adult patients before allo-SCT. Results were correlated with occurrence of aGVHD and relapse. In univariate analysis, iNKT cells were the only graft cell populations associated with occurrence of aGVHD...
April 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Xiangming Li, Moriya Tsuji, Jonathan Schneck, Tonya J Webb
Natural killer T (NKT) cells bridge the innate and adaptive arms of the immune system, and manipulating their effector functions can have therapeutic significances in the treatment of autoimmunity, transplant biology, infectious disease and cancer. This important lymphocyte subset regulates the immune system through their potent cytokine production following the recognition of lipid antigen present in the context of the MHC class I-like CD1d molecule, in addition their ability to directly mediate cytotoxicity...
March 20, 2013: Bio-protocol
Florent Malard, Myriam Labopin, Patrice Chevallier, Thierry Guillaume, Alix Duquesne, Fanny Rialland, Sophie Derenne, Pierre Peterlin, Anne-Gaelle Leauté, Eolia Brissot, Marc Gregoire, Philippe Moreau, Philippe Saas, Béatrice Gaugler, Mohamad Mohty
We studied the impact of a set of immune cells contained within granulocyte colony-stimulating factor-mobilized peripheral blood stem cell grafts (naïve and memory T-cell subsets, B cells, regulatory T cells, invariant natural killer T cells [iNKTs], NK cells, and dendritic cell subsets) in patients (n = 80) undergoing allogeneic stem cell transplantation (SCT), using the composite end point of graft-versus-host disease (GVHD)-free and progression-free survival (GPFS) as the primary end point. We observed that GPFS incidences in patients receiving iNKT doses above and below the median were 49% vs 22%, respectively (P= ...
April 7, 2016: Blood
P Guan, H Bassiri, N P Patel, K E Nichols, R Das
Invariant natural killer T cells (iNKTs) are innate-like lipid-reactive T lymphocytes that express an invariant T-cell receptor (TCR). Following engagement of the iTCR, iNKTs rapidly secrete copious amounts of Th1 and Th2 cytokines and promote the functions of several immune cells including NK, T, B and dendritic cells. Accordingly, iNKTs bridge the innate and adaptive immune responses and modulate susceptibility to autoimmunity, infection, allergy and cancer. Allogeneic hematopoietic stem cell transplantation (HSCT) is one of the most effective treatments for patients with hematologic malignancies...
May 2016: Bone Marrow Transplantation
Ashish K Sharma, Damien J LaPar, Matthew L Stone, Yunge Zhao, Christopher K Mehta, Irving L Kron, Victor E Laubach
RATIONALE: Ischemia-reperfusion (IR) injury after lung transplantation, which affects both short- and long-term allograft survival, involves activation of NADPH oxidase 2 (NOX2) and activation of invariant natural killer T (iNKT) cells to produce IL-17. Adenosine A2A receptor (A2AR) agonists are known to potently attenuate lung IR injury and IL-17 production. However, mechanisms for iNKT cell activation after IR and A2AR agonist-mediated protection remain unclear. OBJECTIVES: We tested the hypothesis that NOX2 mediates IL-17 production by iNKT cells after IR and that A2AR agonism prevents IR injury by blocking NOX2 activation in iNKT cells...
May 1, 2016: American Journal of Respiratory and Critical Care Medicine
T Hirai, R Ishii, S Miyairi, M Ikemiyagi, K Omoto, Y Ishii, K Tanabe
Recently, the immune-regulating potential of invariant natural killer T (iNKT) cells has attracted considerable attention. We previously reported that a combination treatment with a liposomal ligand for iNKT cells and an anti-CD154 antibody in a sublethally irradiated murine bone marrow transplant (BMT) model resulted in the establishment of mixed hematopoietic chimerism through in vivo expansion of regulatory T cells (Tregs). Herein, we show the lack of alloreactivity of CD8(+) T cells in chimeras and an early expansion of donor-derived dendritic cells (DCs) in the recipient thymi accompanied by a sequential reduction in the donor-reactive Vβ-T cell receptor repertoire, suggesting a contribution of clonal deletion in this model...
February 2016: American Journal of Transplantation
Syh-Jae Lin, Ying-Cheng Huang, Po-Jen Cheng, Pei-Tzu Lee, Hsiu-Shan Hsiao, Ming-Ling Kuo
Invariant natural killer T cells (iNKT cells) are innate-like non-conventional T cells restricted by the CD1d molecule that are unique in their ability to play a pivotal role in immune regulation. Deficient iNKT function has been reported in patients receiving umbilical cord blood (UCB) transplantation. We sought to determine the effect of interleukin (IL)-15 on α-galactosylceramide (α-GalCer)-expanded iNKT cell function from UCB and adult peripheral blood (APB) mononuclear cells (MNCs). Fresh APB and UCB MNCs were cultured with IL-15 (50 ng/ml) in the presence or absence of α-GalCer (100 ng/ml) for 10 days...
December 2015: Cytokine
Gregor Blank, Christian Welker, Bence Sipos, Katja Sonntag, Friederike Müller, Franziska Eckert, Christian Seitz, Silvio Nadalin, Gina LaCorcia, Alfred Königsrainer, Daniel Snell, Rupert Handgretinger, Karin Schilbach
GVHD, both acute and chronic, remains the major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation. Thus, there is still a great need for therapeutic tools for the prevention and treatment of GVHD. Several biologics have shown promising results in salvage therapies but are attendant on an increased risk for opportunistic infections, lymphoproliferative disorders, and relapse. This is partly due to efficient T cell elimination that neither dissects alloreactive from non-alloreactive T cells nor considers functional and structural distinctiveness of pathogen- and malignancy-reactive γδ and iNKT T cells...
November 2015: Annals of Hematology
Courtney K Anderson, Alexander I Salter, Leon E Toussaint, Emma C Reilly, Céline Fugère, Neetu Srivastava, William G Kerr, Laurent Brossay
SHIP1 is a 5'-inositol phosphatase known to negatively regulate the signaling product of the PI3K pathway, phosphatidylinositol (3-5)-trisphosphate. SHIP1 is recruited to a large number of inhibitory receptors expressed on invariant NK (iNKT) cells. We hypothesized that SHIP1 deletion would have major effects on iNKT cell development by altering the thresholds for positive and negative selection. Germline SHIP1 deletion has been shown to affect T cells as well as other immune cell populations. However, the role of SHIP1 on T cell function has been controversial, and its participation on iNKT cell development and function has not been examined...
September 1, 2015: Journal of Immunology: Official Journal of the American Association of Immunologists
Sophie Servais, Catherine Menten-Dedoyart, Yves Beguin, Laurence Seidel, André Gothot, Coline Daulne, Evelyne Willems, Loïc Delens, Stéphanie Humblet-Baron, Muriel Hannon, Frédéric Baron
BACKGROUND: Pre-transplant infusion of rabbit anti-T cell globulin (ATG) is increasingly used as prevention of graft-versus-host disease (GVHD) after allogeneic peripheral blood stem cell transplantation (PBSCT). However, the precise impact of pre-transplant ATG on immune recovery after PBSCT is still poorly documented. METHODS: In the current study, we compared immune recovery after myeloablative PBSCT in 65 patients who either received (n = 37) or did not (n = 28) pre-transplant ATG-Fresenius (ATG-F)...
2015: PloS One
Annkristin Heine, Peter Brossart
In this issue of Blood, Schneidawind et al demonstrate that the adoptive transfer of CD4+ invariant natural killer T (iNKT) cells from third-party mice protects from lethal graft-versus-host disease (GVHD) through expansion of donor regulatory T cells (Tregs) in a murine model of allogeneic hematopoietic cell transplantation (HCT).
May 28, 2015: Blood
Dominik Schneidawind, Jeanette Baker, Antonio Pierini, Corina Buechele, Richard H Luong, Everett H Meyer, Robert S Negrin
Graft-versus-host disease (GVHD) is driven by extensive activation and proliferation of alloreactive donor T cells causing significant morbidity and mortality following allogeneic hematopoietic cell transplantation (HCT). Invariant natural killer T (iNKT) cells are a potent immunoregulatory T-cell subset in both humans and mice. Here, we explored the role of adoptively transferred third-party CD4(+) iNKT cells for protection from lethal GVHD in a murine model of allogeneic HCT across major histocompatibility barriers...
May 28, 2015: Blood
S-W Tsaih, M Presa, S Khaja, A E Ciecko, D V Serreze, Y-G Chen
Invariant natural killer T (iNKT)-cell development is controlled by many polymorphic genes present in commonly used mouse inbred strains. Development of type 1 diabetes (T1D) in NOD mice partly results from their production of fewer iNKT-cells compared with non-autoimmune-prone control strains, including ICR. We previously identified several iNKT-cell quantitative trait genetic loci co-localized with known mouse and human T1D regions in a (NOD × ICR)F2 cross. To further dissect the mechanisms underlying the impaired iNKT-cell compartment in NOD mice, we carried out a series of bone marrow transplantation as well as additional genetic mapping studies...
April 2015: Genes and Immunity
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