Direct cloning of leukemia-reactive T cells from patients treated with donor lymphocyte infusion shows a relative dominance of hematopoiesis-restricted minor histocompatibility antigen HA-1 and HA-2 specific T cells

Kloosterboer, Freke M.; Luxemburg-Heijs, Simone A.P. van; Soest, Ronald A. van; Barbui, Anna Maria; Egmond, H.M. van; Strijbosch, M P W; Kester, Michel G.D.; Marijt, W.A.F.; Goulmy, Els; Willemze, R.; Falkenburg, J.H. Frederik

doi:10.1038/sj.leu.2403297

Cited by 58 publications

(60 citation statements)

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“…It is still necessary to optimize culture conditions such as varying peptide length, adjusting the stimulation period for minimizing in vitro clonal contraction and incorporating positive selection before cloning to maximize the chance to identify multiple clones. 36 It would be interesting to know whether HLA-A*0201-restricted HA-1 H -specific CTLs raised by other researchers also fail to recognize the HA-1 H /A*0201 peptide, VLHDDLLEA, presented on HLA-A*0206 and whether our HLA-A*0206-restricted CTL clones that lysed HLA-A*0201 þ and HA-1 H LCL are relatively uncommon. To this end, it would be necessary to randomly raise CTL clones by single cell-sorting T cells strongly stained with either HLA-A*0206/HA-1 H or HLA-A*0201/HA-1 H tetramer.…”

Section: Discussionmentioning

confidence: 98%

The HLA-A0201-restricted minor histocompatibility antigen HA-1H peptide can also be presented by another HLA-A2 subtype, A0206

Torikai

Akatsuka

Miyauchi

et al. 2007

Bone Marrow Transplant

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Section: Discussionmentioning

confidence: 98%

The HLA-A0201-restricted minor histocompatibility antigen HA-1H peptide can also be presented by another HLA-A2 subtype, A0206

Torikai

Akatsuka

Miyauchi

et al. 2007

Bone Marrow Transplant

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“…18 Furthermore, we recently demonstrated that T cells contributing to the GVL reactivity of DLI can be isolated based on their production of IFNg. 36 Thus, Th1 cytokines play a very important role in antitumor reactivity. Th2 and Tc2 cells have also been suggested to play a central role in the regulation of GVHD, graft rejection, and GVL responses.…”

Section: Discussionmentioning

confidence: 99%

HLA class II restricted T-cell receptor gene transfer generates CD4+ T cells with helper activity as well as cytotoxic capacity

et al. 2005

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Both cytotoxic T cells and helper T cells are important in immune responses against pathogens and malignant cells.In hematological malignancies which express HLA class II molecules, immunotherapy may be directed to HLA class II restricted antigens. We investigated whether it is possible to engineer HLA class II restricted T cells with both antigenspecific cytolytic activity and the capacity to produce high amounts of cytokines. CD4 + and CD8 + peripheral-bloodderived T cells were retrovirally transduced with the HLA class II restricted minor histocompatibility antigen dead box RNA helicase Y (DBY)-specific TCR. The TCR-transduced CD4 + T cells exerted DBY-specific cytolytic activity, produced Th0, Th1, or Th2 cytokines, and proliferated upon DBY-specific stimulation. TCR-transduced CD8 + T cells exerted cytolytic activity which equaled the level of cytolytic activity of the TCR-transferred CD4 + T cells. Cotransfer of CD4 enhanced the cytolytic activity of the TCR-transduced CD8 + T cells, but introduction of CD4 was not sufficient to generate DBY-specific CD8 + T cells with the capacity to produce high amounts of cytokines. In this study, we demonstrated the feasibility to engineer T cells with antigen-specific cytolytic activity, as well as the ability to produce significant amounts of cytokines, by TCR transfer to CD4 + T cells. Gene Therapy (2005) IntroductionPatients relapsing from leukemia after allogeneic stem cell transplantation can successfully be treated by donor lymphocyte infusions (DLI), due to the graft-versusleukemia (GVL) response of the donor-derived T cells. [1][2][3][4] However, DLI is also associated with graft-versus-hostdisease (GVHD). Several studies have illustrated that depletion of CD8 + T cells from the DLI may preserve the beneficial GVL reactivity without the induction of GVHD, indicating that the CD4 + T lymphocytes may play an essential role in the antileukemic reactivity. [5][6][7][8][9][10] The mechanism by which the CD4 + T cells contribute to the GVL response is, however, not known. CD4 + T cells have been suggested to elicit the antileukemic response via the induction of minor histocompatibility antigen (mHag)-specific CD8 + T cells. 5 In addition, mHag-specific CD4 + T-helper cells have been reported to mature dendritic cells and enhance the expansion of mHag-specific cytotoxic T lymphocytes in vitro. 11 Alternatively, we have demonstrated that CD4 + T cells are capable of exerting direct cytolytic activity against leukemic cells. [12][13][14] Cellular immunotherapeutic approaches based on the adoptive transfer of T lymphocytes may require large cell numbers. Large numbers of T cells with a defined antigen specificity can be acquired by retroviral transfer of the T-cell receptor to peripheral-blood-derived T lymphocytes. Until now, the application of retroviral transfer of TCRs has mainly been limited to the transfer of HLA class I restricted TCRs. [15][16][17][18][19][20] However, the specificity of HLA class II restricted T lymphocytes can also be transferred to other T c...

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“…[8][9][10][11] However, CD4 þ T cells with direct cytolytic activity against leukemic cells have been isolated from patients with GvL responses, suggesting that CD4 þ T cells may also contribute to anti-tumor immunity as effector cells. 7,[12][13][14] This is also supported by clinical studies, which showed that depletion of CD8 þ T cells from the stem cell graft or DLI reduced the incidence and severity of GvHD without compromising GvL reactivity. 15,16 However, although these studies have demonstrated clinical efficacy of CD8-depleted DLI, it remains unclear whether clinical responses in these patients were directly mediated by CD4 þ T cells, or could be attributed to contaminating CD8 þ T cells in the DLI or residual donor-derived CD8 þ T cells in the patients.…”

Section: Introductionmentioning

confidence: 86%

Human allo-reactive CD4+ T cells as strong mediators of anti-tumor immunity in NOD/scid mice engrafted with human acute lymphoblastic leukemia

et al. 2011

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Adoptive immunotherapy with donor lymphocyte infusion (DLI) after allogeneic stem cell transplantation (alloSCT) may not only mediate Graft-versus-Leukemia (GvL) reactivity, but also induce Graft-versus-Host Disease (GvHD). As HLA-class II molecules are predominantly expressed on hematopoietic cells, CD4 þ T cells may selectively mediate GvL reactivity without GvHD. Here, we assessed the capacity of human CD4 þ T cells to act as sole mediators of GvL reactivity in a NOD/scid mouse model for human acute lymphoblastic leukemia and chronic myeloid leukemia in lymphoid blast crisis. Highly purified CD4 þ DLI eradicated the leukemic cells. The anti-tumor immunity was mediated by a polyclonal CD4 þ T cell response comprising cytokine-producing T-helper and cytolytic T-effector cells directed against the mismatched HLA-class II molecules of the patients. Furthermore, primary leukemic cells acquired an antigen-presenting cell (APC) phenotype in vivo after DLI, as well as in vitro after co-culture with leukemia-specific CD4 þ T cells. In conclusion, our results show that CD4 þ T cells can be strong mediators of anti-tumor immunity, and provide evidence that cross-talk between CD4 þ T cells and leukemic cells is the basis for induction of leukemic cells with an APC phenotype. These data emphasize the clinical relevance of CD4 þ T cell based immunotherapy as treatment modality for hematological malignancies after alloSCT.

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Direct cloning of leukemia-reactive T cells from patients treated with donor lymphocyte infusion shows a relative dominance of hematopoiesis-restricted minor histocompatibility antigen HA-1 and HA-2 specific T cells

Cited by 58 publications

References 50 publications

The HLA-A0201-restricted minor histocompatibility antigen HA-1H peptide can also be presented by another HLA-A2 subtype, A0206

The HLA-A0201-restricted minor histocompatibility antigen HA-1H peptide can also be presented by another HLA-A2 subtype, A0206

HLA class II restricted T-cell receptor gene transfer generates CD4+ T cells with helper activity as well as cytotoxic capacity

Human allo-reactive CD4+ T cells as strong mediators of anti-tumor immunity in NOD/scid mice engrafted with human acute lymphoblastic leukemia

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Direct cloning of leukemia-reactive T cells from patients treated with donor lymphocyte infusion shows a relative dominance of hematopoiesis-restricted minor histocompatibility antigen HA-1 and HA-2 specific T cells

Cited by 58 publications

References 50 publications

The HLA-A*0201-restricted minor histocompatibility antigen HA-1H peptide can also be presented by another HLA-A2 subtype, A*0206

The HLA-A*0201-restricted minor histocompatibility antigen HA-1H peptide can also be presented by another HLA-A2 subtype, A*0206

HLA class II restricted T-cell receptor gene transfer generates CD4+ T cells with helper activity as well as cytotoxic capacity

Human allo-reactive CD4+ T cells as strong mediators of anti-tumor immunity in NOD/scid mice engrafted with human acute lymphoblastic leukemia

Contact Info

Product

Resources

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The HLA-A0201-restricted minor histocompatibility antigen HA-1H peptide can also be presented by another HLA-A2 subtype, A0206

The HLA-A0201-restricted minor histocompatibility antigen HA-1H peptide can also be presented by another HLA-A2 subtype, A0206