HLA-DP as specific target for cellular immunotherapy in HLA class II-expressing B-cell leukemia

Rutten, Caroline E.; Luxemburg-Heijs, Simone A.P. van; Griffioen, Marieke; Marijt, Erik W.A.; Jedema, Inge; Heemskerk, Mirjam H.M.; Posthuma, E. F. M.; Willemze, R.; Falkenburg, J. H. F.

doi:10.1038/leu.2008.90

Cited by 52 publications

(65 citation statements)

References 36 publications

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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: Introductionsupporting

confidence: 51%

“…7,14 Therefore, we postulate that in the early posttransplantation period, HLA-class II expression on non-hematopoietic cells may be upregulated by proinflammatory cytokines produced at high levels as a result of tissue damage induced by transplant conditioning regimens or infections. Infusion of HLA-class II mismatched donor CD4 þ T cells in the early posttransplantation period may therefore have a high risk for the development of GvHD.…”

Section: Discussionmentioning

confidence: 99%

“…However, we have previously demonstrated that, in the absence of an inflammatory environment, HLA-DP-specific allo-reactive CD4 þ T cells mediated a strong GvL response with only minimal skin GvHD in a patient who responded to unmodified DLI administered late after HLA-DP mismatched T cell depleted alloSCT. 7 Development of GvL reactivity and GvHD is therefore likely to depend on the expression pattern of HLA-DR, -DQ and -DP molecules on normal and malignant cells that may be variable under different clinical circumstances. Therefore, insight into the contribution of HLA-class II molecules to GvL reactivity and GvHD is relevant for optimal design of CD4 þ T cell based immunotherapies after HLA-class II mismatched alloSCT.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Introductionsupporting

confidence: 51%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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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“…6 This finding might be explained by more selective immune reactions of donorderived CD4 T cells recognizing allo-peptides on HLA class II molecules that are preferentially expressed by recipient hematopoietic cells, but not by epithelial cells under noninflammatory conditions. 28 In addition, the absolute T-cell counts after alemtuzumab-based conditioning are significantly lower than that after T-cell-replete transplantation, which might facilitate the influence of DLI-derived T cells on donor TCC. Data from small trials so far suggest that CD8 depl DLI might induce comparably low rates of GVHD, while retaining the beneficial DLI activity.…”

Section: Resultsmentioning

confidence: 99%

Donor CD4 T cells convert mixed to full donor T-cell chimerism and replenish the CD52-positive T-cell pool after alemtuzumab-based T-cell-depleted allo-transplantation

Meyer

Wagner

Konur

et al. 2009

Bone Marrow Transplant

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Donor lymphocyte infusions (DLI) are used to resolve mixed T-cell chimerism (TCC) after allo-SCT despite a substantial risk of GVHD. We analyzed the impact of prophylactic CD8-depleted (CD8 depl ) DLI in 20 recipients of anti-CD52 alemtuzumab in vivo T-cell-depleted allografts with declining donor TCC after day þ 60. A total of 13 patients received CD8 depl DLI and 7 patients did not. All but one of the DLI patients converted to complete donor T-cell chimeras, whereas only one non-DLI patient converted spontaneously. DLI induced transient acute GVHD in five and extensive chronic GVHD in two patients. These data suggest the use of CD8 depl DLI as an effective treatment for mixed TCC, particularly in patients at high risk for GVHD. We also observed that the majority of reconstituting donor-derived T cells after alemtuzumab conditioning were CD52-negative. CD8 depl DLI significantly increased the proportion of CD52-positive CD4 T cells, whereby their beneficial effect on reconstituting the post-transplant T-cell repertoire was shown.

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“…In transplant setting allogeneic HLA-DP-specific T cells have been identified in both GVHD and GVL cases. [6][7][8][9] However, the importance of this locus, as a transplantation antigen remained poorly understood. One of the reasons that this antigen has received less attention is the weak linkage disequilibrium, dependent on a recombination hot spot between the HLA-DQ and DP loci.…”

Section: Discussionmentioning

confidence: 99%

Impact of HLA-DPB1 Matching in Unrelated Allogeneic Stem Cell Transplantation: Results of Two Centers From Turkey

Kantarcıoğlu¹

2017

UHOD

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In this study, we retrospectively examined 34 donor/recipient transplant pairs fully tested for the alleles HLA-A, B, C, DRB1, DQB1 and DPB1 in two different centers in Istanbul, Turkey. HLA-DPB1 disparity in at least one antigen level was 79.6% and only 20.6% of transplant pairs were fully identical for HLA-DPB1, in our study group. Neutrophil and thrombocyte engraftment successfully occurred in the entire study group. When the occurrence of severe (Grade III-IV) aGVHD was taken into account, we have observed that, non-permissive HLA-DPB1 mismatches were a significant factor for development of severe aGVHD (p= 0.019). There was a trend of increasing significance for the gut (p= 0.006) and liver (p: 0.054) aGVHD but not for skin aGVHD in non-permissive HLA-DPB1 mismatched transplantations. In multivariate analysis, non-permissive HLA-DPB1 mismatches remained as an independent factor for severe aGVHD. Our results did not show a significant impact of HLA-DPB1 mismatches on relapse. In survival analysis, both HLA-DPB1 disparities and non-permissive mismatches showed a decreasing trend of event free and overall survival times. Considering these results during donor selection may improve transplant outcomes in the setting of unrelated ASCT.

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HLA-DP as specific target for cellular immunotherapy in HLA class II-expressing B-cell leukemia

Cited by 52 publications

References 36 publications

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

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

Donor CD4 T cells convert mixed to full donor T-cell chimerism and replenish the CD52-positive T-cell pool after alemtuzumab-based T-cell-depleted allo-transplantation

Impact of HLA-DPB1 Matching in Unrelated Allogeneic Stem Cell Transplantation: Results of Two Centers From Turkey

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