Hematopoiesis-restricted minor histocompatibility antigens HA-1- or HA-2-specific T cells can induce complete remissions of relapsed leukemia

Marijt, W. A. Erik; Heemskerk, Mirjam H.M.; Kloosterboer, Freke M.; Goulmy, Els; Kester, Michel G.D.; Hoorn, Menno A.W.G. van der; Luxemburg-Heys, S. A. P. Van; Hoogeboom, Manja; Mutis, Tuna; Drijfhout, Jan W.; Rood, Jon J. van; Willemze, R.; Falkenburg, J.H. Frederik

doi:10.1073/pnas.0530192100

Cited by 383 publications

(302 citation statements)

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“…Such T REG may impair HA-1 or HA-2 T CTL -driven graft-versus-leukemia reactions. 34,35 Evidently, the presence of these T REG must also be considered when HA-1-or HA-2-specific T CTL are generated from unselected PBMCs or CD8-enriched populations for the purpose of cellular adoptive immunotherapy. 36 Given our current observations that nonfunctional CD8 ϩ T cells, ie, failure to lyse or produce interferon-␥ when stimulated with minor H alloantigen, can also be expanded from some of our donors (&2, &3, and (2, data not shown), we speculate that naturally established tolerance to minor H antigens may be the result of either the presence of minor H antigen-specific T REG and/or the induction of T-cell anergy.…”

Section: Discussionmentioning

confidence: 99%

Naturally acquired tolerance and sensitization to minor histocompatibility antigens in healthy family members

Halteren

Jankowska‐Gan

Joosten

et al. 2009

Blood

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Bidirectional cell transfer during pregnancy frequently leads to postpartum persistence of allogeneic cells and alloimmune responses in both the mother and in her offspring. The life-long consequences of naturally acquired alloimmune reactivity are probably of importance for the outcome of allogeneic stem cell transplantation. We investigated the presence of CD8 pos minor histocompatibility (H) antigen-specific cytotoxic T lymphocytes (T CTL ) and CD8 pos minor H antigen-specific T regulator cells (T REG ) in peripheral blood cells obtained from 17 minor H antigen-disparate mother-offspring pairs. Absence of minor H antigen-specific T REG , as marked by the feasibility to expand T CTL from isolated tetramer pos populations, was observed in 6 mothers and 1 son. The presence of minor H alloantigen-specific T REG was observed in 4 mothers and 5 sons.These T REG were detected within isolated tetramer dim staining fractions and functioned in a CTLA-4-dependent fashion. Our study indicates that both T CTL and T REG mediated alloimmunity against minor H antigens may be present in healthy female and male hematopoietic stem cell donors, potentially influencing graftversus-host reactivity in different ways.

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Section: Discussionmentioning

confidence: 99%

Naturally acquired tolerance and sensitization to minor histocompatibility antigens in healthy family members

Halteren

Jankowska‐Gan

Joosten

et al. 2009

Blood

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“…[3][4][5][6] Moreover, cytotoxic T lymphocytes (CTLs) directed against these mHags do not cause graft-versus-host disease in an ex vivo skin explant model, 7 and coincide with complete remission of relapsed leukemia and multiple myeloma after HLA-matched HA-1-or HA-2-mismatched donor lymphocyte infusions. 8 HA-1-and HA-2-specific CTLs can be generated in vitro using peptide-pulsed or mHag-transduced autologous dendritic cells (DCs) as antigen-presenting cells (APCs). 9,10 However, expansion of CTLs is difficult due to the limited availability of donor-derived DCs.…”

Section: Introductionmentioning

confidence: 99%

Artificial antigen-presenting constructs efficiently stimulate minor histocompatibility antigen–specific cytotoxic T lymphocytes

Oosten

Blokland

Halteren

et al. 2004

Blood

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Cytotoxic T lymphocytes (CTLs) specific for hematopoietic-restricted minor histocompatibility antigens (mHags) are important reagents for adoptive immunotherapy of relapsed leukemia after allogeneic stem cell transplantation. However, expansion of these CTLs to therapeutic numbers is often hampered by the limited supply of antigen-presenting cells (APCs). Therefore, we evaluated whether cell-sized latex beads coated with HLA/mHag complexes HLA-A2/HA-1 or HLA-A2/HA-2 and recombinant CD80 and CD54 molecules can replace professional APCs. The artificial antigen-presenting constructs (aAPCs) effectively stimulated HA-1-and HA-2-specific CTL clones as shown by ligand-specific expansion, cytokine production, and maintenance of cytotoxic activity, without alteration of CTL phenotype. Furthermore, HA-1-specific polyclonal CTL lines were enriched as effi- IntroductionThe successful application of donor lymphocyte infusions for the treatment of relapsed leukemia after allogeneic stem cell transplantation illustrates the feasibility of adoptive immunotherapy of hematologic malignancies. 1 To minimize graft-versus-host disease, we earlier proposed the use of minor histocompatibility antigens (mHags) HA-1 and HA-2 as immunotherapeutic reagents. 2 HA-1 and HA-2 display hematopoietic-restricted tissue distribution and relevant expression on leukemic cells and their progenitors. [3][4][5][6] Moreover, cytotoxic T lymphocytes (CTLs) directed against these mHags do not cause graft-versus-host disease in an ex vivo skin explant model, 7 and coincide with complete remission of relapsed leukemia and multiple myeloma after HLA-matched HA-1-or HA-2-mismatched donor lymphocyte infusions. 8 HA-1-and HA-2-specific CTLs can be generated in vitro using peptide-pulsed or mHag-transduced autologous dendritic cells (DCs) as antigen-presenting cells (APCs). 9,10 However, expansion of CTLs is difficult due to the limited availability of donor-derived DCs. To date, several reports indicate effective stimulation of T cells by HLA/peptide ligands expressed on artificial antigenpresenting constructs (aAPCs) such as liposomes 11,12 or microbeads. [13][14][15][16] We developed aAPCs that can be manufactured under good manufacturing practice conditions and used to expand mHag-specific CTLs for adoptive immunotherapy. Hereto, cell-sized latex microbeads coated with HLA-A2/HA-1 or HLA-A2/HA-2 complexes, CD80, and CD54 were investigated for their potential to efficiently stimulate HA-1-and HA-2-specific CTL clones and lines while keeping their antigenspecific cytolytic properties. Study design mHag-specific CTL clones and polyclonal CTL lines, CD4 ؉ T helper cells, and DCsIn vivo and in vitro generation of mHag-specific CTL clones, polyclonal CTL lines, and DCs is documented in detail elsewhere. 9,17 CD4 ϩ T-helper cells (CD4 ϩ Th cells) were generated by culturing peripheral blood mononuclear cells (PBMCs) for 14 days in Iscove modified Dulbecco medium (IMDM) containing 10% pooled human serum (HS) and 0.5% standard Dutch diphtheria/pertussis/tetanus/po...

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“…DISCUSSION mHA are considered to have a dominant role in mediating graftversus-tumor reactivity after HLA-identical allo-SCT for hematological malignancies. 15,16,17 Recently, we demonstrated that partial T-cell-depleted allogeneic RIC --SCT creates a platform for inducing graft-versus-tumor immunity by post-transplant immunotherapy in patients suffering from MM. Escalating dose DLI could be given to most patients (63%) and vaccination with KLH-loaded recipient DCs was explored in six patients.…”

Section: Case Descriptionmentioning

confidence: 99%

Induction of multiple myeloma-reactive T cells during post-transplantation immunotherapy with donor lymphocytes and recipient DCs

Broen

Greupink-Draaisma

Fredrix

et al. 2012

Bone Marrow Transplant

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Recently, we demonstrated that reduced intensity conditioning (RIC) followed by partial T-cell-depleted SCT creates a platform for inducing the graft-versus-myeloma effect by adjuvant immunotherapy. Here, we evaluated mHA-specific T-cell responses in a multiple myeloma (MM) patient who was treated with RIC --SCT followed by donor lymphocyte infusion (DLI) and subsequent recipient DC vaccination. We isolated a mHA-specific CTL clone with the capacity to target MM tumor cells from this patient experiencing long-term CR. This CTL clone recognizes an HLA-A3-restricted mHA and mediates killing of both primary MM cells and the MM-cell line U266, while BM-derived fibroblasts are not recognized. CTL-specific T-cell receptor (TCR) transcripts could be detected by quantitative PCR analysis in both peripheral blood and BM during tumor remission. Interestingly, a strong increase of CTL-specific TCR transcripts at the BM tumor site was observed following DLI and recipient DC vaccination, while the TCR signal in peripheral blood decreased. These findings illustrate that the approach of partial T-cell-depleted RIC --SCT followed by post-transplantation immunotherapy induces mHA-specific T-cell responses targeting MM tumor cells. Keywords: graft-versus-tumor; minor histocompatibility antigen; multiple myeloma; immunotherapy; cytotoxic T cells; DCs INTRODUCTIONAllo-SCT has the potential to cure patients with multiple myeloma (MM) due to the graft-versus-myeloma (GVM) effect. 1,2 This GVM effect can be mediated by alloreactive donor T cells targeting mHA expressed on myeloma tumor cells in the BM. Previously, we have established the potential of partial T-cell-depleted allo-SCT followed by pre-emptive donor lymphocyte infusion (DLI) to induce GVM immunity with limited risk of inducing GVHD. These studies showed that long-term CR can be induced in about one third of MM patients. 3 To further improve these results, we have explored the possibility of boosting GVM immunity, without the toxicity and morbidity due to GVHD, by means of recipient DC vaccination post-DLI. Although we showed that mature recipientderived DC could be generated, and that vaccination resulted in limited toxicity, no obvious direct effects on tumor load could be demonstrated. 4 In the setting of using unloaded recipient-derived DC vaccines, we aimed at the induction of alloreactive donor T-cell responses against both known and unknown mHA on myeloma tumor cells of the recipient. Previously, it has been reported that mHA-specific CTL isolated from transplanted MM patients are able to target mHA, like HA-1, 5 ADIR 6 and ECGF, 7 that are co-expressed by MM tumor cells and monocyte-derived DCs. In this study, we investigated mHA-specific-CD8 þ T-cell responses in a MM patient who successfully obtained long-term clinical remission (CR) in the absence of GVHD after treatment with reduced intensity conditioning (RIC) --SCT followed by DLI and recipient DC vaccination. Following DC vaccination, primary T-cell responses were elicited against keyhole limpet hemocyanin (...

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Hematopoiesis-restricted minor histocompatibility antigens HA-1- or HA-2-specific T cells can induce complete remissions of relapsed leukemia

Cited by 383 publications

References 46 publications

Naturally acquired tolerance and sensitization to minor histocompatibility antigens in healthy family members

Naturally acquired tolerance and sensitization to minor histocompatibility antigens in healthy family members

Artificial antigen-presenting constructs efficiently stimulate minor histocompatibility antigen–specific cytotoxic T lymphocytes

Induction of multiple myeloma-reactive T cells during post-transplantation immunotherapy with donor lymphocytes and recipient DCs

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