Peripheral blood progenitor cell product contains Th1-biased noninvariant CD1d-reactive natural killer T cells: Implications for posttransplant survival

Abstract

OBJECTIVE-Bone marrow (BM) Th1 populations can contribute to graft-versus-leukemia (GvL) responses. G/GM-CSF-mobilized peripheral blood progenitor cells (PBPC) have become widely accepted alternatives to BM transplantation (BMT). T cells co-expressing NK proteins (NKT) include a CD1d-reactive subset which influence immunity by rapidly producing large amounts of Th1 and/ or Th2 cytokines dependent upon microenvironment and disease. There are two types of CD1d-reactive NKT. "iNKT" express a semi-invariant TCR-α. Other "non-invariant" CD1d-reactive NKT from BM and liver produce large amounts of IL-4 or IFN-γ respectively, and within the intestine can be biased in either direction. Recent data suggests that NKT might contribute to clinical benefits of PBPC.METHODS-To address these issues, we phenotypically and functionally studied PBPC NKT.RESULTS-Similarly to BM, NKT-like cells were common in allogeneic and autologous PBPC, there were relatively few classical iNKT, but high CD1d-reactivity concentrated in NKT fractions. Significantly, PBPC CD1d-reactive cells were relatively Th1-biased and their presence was associated with better prognosis. G-CSF treatment of BM to yield PBPC in vivo as well as in vitro Th2-polarizes conventional T cells and iNKT. However, G-CSF treatment of BM in vitro produced Th1-biased NKT, providing a mechanism for opposite polarization of NKT from BM versus PBPC.CONCLUSIONS-These results suggest distinct Th1 CD1d-reactive NKT cells could stimulate anti-tumor responses from those previously described, which can suppress GvHD.

Circulating Myeloid Dendritic Cells of Advanced Cancer Patients Result in Reduced Activation and a Biased Cytokine Profile in Invariant NKT Cells

“…In this study we show that circulating mDC1 of patients with advanced melanoma and renal cell cancer resulted in reduced activation and a biased cytokine profile in healthy donor-derived iNKT cells, suggesting that this defective interaction contributes to the previously observed qualitative and quantitative defects in iNKT cells of cancer patients (7)(8)(9)(10)(11)(12)(13)(14). This is underscored by the observation that only the mDC1 of cancer patients with low circulating iNKT cell numbers, but not the mDC1 of cancer patients with normal circulating iNKT cell numbers, resulted in this biased iNKT cell response, indicating that the circulating iNKT cell frequency of cancer patients appears to reflect the Ag-presenting quality of their circulating mDC1.…”

“…[1][2][3][4][5][6]. Importantly, the circulating pool of iNKT cells shows quantitative and qualitative defects in cancer patients independent of tumor type and tumor load (7)(8)(9)(10), and these defects are clinically relevant as increased numbers of intratumoral or circulating iNKT cells are associated with improved prognosis in colon cancer, head and neck squamous cell carcinoma, hematological malignancies, and neuroblastoma (11)(12)(13)(14). Several studies indicate that the residual pool of iNKT cells of cancer patients is Th2 biased, although this might not be the case in all types of cancer (8 -10).…”

Emergency granulopoiesis promotes neutrophil-dendritic cell encounters that prevent mouse lung allograft acceptance

“…31 A similar report demonstrated that G-CSF could also directly stimulate natural killer T cells to promote Th1 responses. 32 Therefore, it remains possible that G-CSF may partly promote Th1 responses in a manner independent of neutrophil-mediated IL-12 production by DCs after lung transplantation. In addition, G-CSF administration may have direct effects on CD4 ϩ T cells, mainly biasing them toward Th2 polarization [33][34][35] in cases where this agent is used to harvest hematopoietic progenitors.…”

High dose chemotherapy with autologous stem cell support for patients with histologically transformed B‐cell non‐Hodgkin lymphomas. A Norwegian multi centre phase II study

“…We identified no significant differences in these parameters between the patients receiving purged and nonpurged grafts. One may further speculate whether the in vitro purging by positive selection of CD34 + cells itself exerts a negative effect, possibly by removal of tumour-reactive T-cell subsets (Shaulov et al, 2008) and natural killer cells (Porrata et al, 2008). In eight of 32 patients mobilization of CD34 + stem cells was insufficient (25%) and treatment with ‡2 chemotherapy courses prior to inclusion reduced the odds for obtaining sufficient numbers of CD34 + stem cells by leukaphaeresis, in line with previous findings by us and others (Haas et al, 1994;Aurlien et al, 1998Aurlien et al, , 2001Ketterer et al, 1998;Moskowitz et al, 1998).…”