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Cardiomyocytes Derived from MHC-Homozygous Induced Pluripotent Stem Cells Exhibit Reduced Allogeneic Immunogenicity in MHC-Matched Non-human Primates.

ABSTRACT: Induced pluripotent stem cells (iPSCs) can serve as a source of cardiomyocytes (CMs) to treat end-stage heart failure; however, transplantation of genetically dissimilar iPSCs even within species (allogeneic) can induce immune rejection. We hypothesized that this might be limited by matching the major histocompatibility complex (MHC) antigens between the donor and the recipient. We therefore transplanted fluorescence-labeled (GFP) iPSC-CMs donated from a macaque with homozygous MHC haplotypes into the subcutaneous tissue and hearts of macaques having heterozygous MHC haplotypes (MHC-matched; group I) or without identical MHC alleles (group II) in conjunction with immune suppression. Group I displayed a higher GFP intensity and less immune-cell infiltration in the graft than group II. However, MHC-matched transplantation with single or no immune-suppressive drugs still induced a substantial host immune response to the graft. Thus, the immunogenicity of allogeneic iPSC-CMs was reduced by MHC-matched transplantation although a requirement for appropriate immune suppression was retained for successful engraftment.

SUBMITTER: Kawamura T

PROVIDER: S-EPMC4788782 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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Cardiomyocytes Derived from MHC-Homozygous Induced Pluripotent Stem Cells Exhibit Reduced Allogeneic Immunogenicity in MHC-Matched Non-human Primates.

Kawamura Takuji T Miyagawa Shigeru S Fukushima Satsuki S Maeda Akira A Kashiyama Noriyuki N Kawamura Ai A Miki Kenji K Okita Keisuke K Yoshida Yoshinori Y Shiina Takashi T Ogasawara Kazumasa K Miyagawa Shuji S Toda Koichi K Okuyama Hiroomi H Sawa Yoshiki Y

Stem cell reports 20160218 3

Induced pluripotent stem cells (iPSCs) can serve as a source of cardiomyocytes (CMs) to treat end-stage heart failure; however, transplantation of genetically dissimilar iPSCs even within species (allogeneic) can induce immune rejection. We hypothesized that this might be limited by matching the major histocompatibility complex (MHC) antigens between the donor and the recipient. We therefore transplanted fluorescence-labeled (GFP) iPSC-CMs donated from a macaque with homozygous MHC haplotypes in ...[more]

PMID: 26905198

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Project description:Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is complicated by graft- versus-host disease (GVHD), which causes immune dysfunction and further delays immune reconstitution through its effects on primary and secondary lymphoid organs. Treatments to prevent GVHD and improve immune recovery following allo-HSCT are needed. Post-transplantation cyclophosphamide (PTCy) is a well-established and clinically widely used method for GVHD prophylaxis after HLA-matched as well as haploidentical allo-HSCT, as well as a promising strategy in the setting of mismatched unrelated donor allo-HSCT. Recently, regulatory T cells (Tregs), a critical subset for immune homeostasis and tolerance induction, have been evaluated for use as GVHD prophylaxis in experimental models and clinical trials. Natural killer (NK) cells are one of the first lymphoid populations to reconstitute following allo-HSCT and are important mediators of protective immunity against pathogens, and are also critical for limiting post-transplantation relapse of hematologic cancers. Several reports have noted that a delay in NK cell recovery may occur following experimental mouse allo-HSCT as well as after clinical allo-HSCT. Here we examined how 2 treatment strategies, PTCy and donor expanded Tregs (TrED), in experimental MHC-matched allo-HSCT affect NK recovery. Our experiments show that both strategies improved NK cell numbers, with PTCy slightly better than TrED, early after allo-HSCT (1 month) compared with untreated allo-HSCT recipients. Importantly, NK cell IFN-γ production and cytotoxic function, as reflected by CD107 expression as well as in vivo killing of NK-sensitive tumor cells, were improved using either PTCy or TrED versus control allo-HSCT recipients. In conclusion, both prophylactic treatments were found to be beneficial for NK recovery and NK cell function following MHC-matched minor antigen-mismatched experimental allo-HSCT. Improved NK recovery could help provide early immunity toward tumors and pathogens in these transplant recipients.

Project description:Human induced pluripotent stem cell (iPSC)-derived endothelial cells (ECs) have emerged as a promising source of autologous cells with great potential to produce novel cell therapy for ischemic vascular diseases. However, their clinical application still faces numerous challenges including safety concerns such as the potential aberrant immunogenicity derived from the reprogramming process. This study investigated immunological phenotypes of iPSC-ECs by a side-by-side comparison with primary human umbilical vein ECs (HUVECs). Three types of human iPSC-ECs, NIBSC8-EC generated in house and two commercial iPSC-ECs, alongside HUVECs, were examined for surface expression of proteins of immune relevance under resting conditions and after cytokine activation. All iPSC-EC populations failed to express major histocompatibility complex (MHC) Class II on their surface following interferon-gamma (IFN-γ) treatment but showed similar basal and IFN-γ-stimulated expression levels of MHC Class I of HUVECs. Multiple iPSC-ECs also retained constitutive and tumor necrosis factor-alpha (TNF-α)-stimulated expression levels of intercellular adhesion molecule-1 (ICAM-1) like HUVECs. However, TNF-α induced a differential expression of E-selectin and vascular cell adhesion molecule-1 (VCAM-1) on iPSC-ECs. Furthermore, real-time monitoring of proliferation of human peripheral blood mononuclear cells (PBMCs) cocultured on an endothelial monolayer over 5 days showed that iPSC-ECs provoked distinct dynamics of PBMC proliferation, which was generally decreased in alloreactivity and IFN-γ-stimulated proliferation of PBMCs compared with HUVECs. Consistently, in the conventional mixed lymphocyte reaction (MLR), the proliferation of total CD3+ and CD4+ T cells after 5-day cocultures with multiple iPSC-EC populations was largely reduced compared to HUVECs. Last, multiple iPSC-EC cocultures secreted lower levels of proinflammatory cytokines than HUVEC cocultures. Collectively, iPSC-ECs manifested many similarities, but also some disparities with a generally weaker inflammatory immune response than primary ECs, indicating that iPSC-ECs may possibly exhibit hypoimmunogenicity corresponding with less risk of immune rejection in a transplant setting, which is important for safe and effective cell therapies.

Dataset Information

Cardiomyocytes Derived from MHC-Homozygous Induced Pluripotent Stem Cells Exhibit Reduced Allogeneic Immunogenicity in MHC-Matched Non-human Primates.

Publications

Cardiomyocytes Derived from MHC-Homozygous Induced Pluripotent Stem Cells Exhibit Reduced Allogeneic Immunogenicity in MHC-Matched Non-human Primates.

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