Summary:ABMT may contribute to an improved clinical outcome. Further, patients receiving a PSCT may be more A majority of patients with intermediate or high-grade responsive to adjuvant immunotherapy following transnon-Hodgkin's lymphoma (NHL) who are treated with plantation. high-dose chemotherapy (HDT) and hematopoietic stem Keywords: PSCT; BMT; immunity; T cell; NHL; NK cell transplantation subsequently relapse. Until recently, cell F transplantation was associated with high morbidity and mortality and the focus was on improving the safety of this procedure. However, the use of growth factors and other supportive measures has successfully reduced High-dose chemotherapy (HDT) supported by hematopotreatment mortality to less than 5%. Therefore, new ietic stem cell transplantation and growth factor adminisstrategies need to be developed to eliminate the growth tration is increasingly used for patients with cancer. 1-3 Leuof any occult tumor cells reinfused with the stem cell kocyte and platelet recovery is more rapid following products and the tumor cells remaining in the patient.peripheral blood stem cell transplantation (PSCT) as comOne approach is to improve the immune function of the pared to bone marrow autografts (ABMT), if the peripheral patients by a more rapid immune reconstitution and stem cells (PSC) are collected after mobilization with hemaugmentation of effector cell function. We report studatopoietic growth factors, chemotherapy, or both. [4][5][6][7][8] In ies comparing immune recovery following HDT and addition, one retrospective study suggested an increase in autologous peripheral stem cell transplantation (PSCT) the progression-free interval following PSCT with steady as compared to autologous bone marrow transplanstate PSC as compared to ABMT, 9 although this obsertation (ABMT). These studies examined patients with vation requires confirmation as well as demonstration in a intermediate and high-grade non-Hodgkin's lymphoma prospectively randomized trial. 4,10,11 (NHL) who were treated with HDT and PSCT (n = 56) PSCT 6,12 may result in an earlier reconstitution of or ABMT (n = 60). The PSCT patients had a signifiimmune function following HDT as compared to cantly faster recovery of circulating monocytes (CD14 + ABMT 13,14 perhaps due to the lymphocytes that are trans- cells), natural killer ((NK) CD56 + ) cells, T helper (CD4 + )fused in the PSC product. To date, there have been limited cells, TCR␥/␦ cells, and naive T lymphocytes and conflicting studies on immune reconstitution following (CD45RA + ). Following ABMT there was a significantly PSCT and ABMT in humans. [15][16][17][18] Overall, there appears to more rapid increase in the frequency of T be wide phenotypic variability of cells in the suppressor/effector (CD8 + ) cells, B (CD19 + ) cells, CD34 + apheresis/transplant products themselves. 14 A significant cells, polymorphonuclear leukocytes (PMN) and memincrease in the frequency of CD8 + cells in the peripheral ory T lymphocytes (CD45RO + ). The CD4:CD8 and blood (PB) following both f...
NIH/3T3 cells transfected with DNA from malignant human tumors produced experimental and spontaneous metastases in nude mice. In contrast, parent or spontaneously transformed NIE/3T3 cells failed to metastasize. The transfected clones contained either activated c-Harvey-ras or N-ras oncogenes. A representative clone (T71-17SA2) which was used to assess selected cellular and host factors relevant to the metastatic process produced lung metastases in 100% of the NIH nude mice recipients, secreted augmented levels of type IV collagenase, and invaded human amnion basement membrane in vitro. Expression of the metastatic phenotype was not related to decreased sensitivity to natural killer cells or macrophage-mediated cytotoxicity. Analysis of the cellular DNA from the T71-17SA2 transfectant and its corresponding metastases, both of which contained activated N-ras oncogenes, revealed a twofold increase in the N-ras-specific DNA sequences in the metastatic cells. Thus, transfection with human tumor DNA containing activated ras oncogenes can induce the complete metastatic phenotype in NIH/3T3 cells by a mechanism apparently unrelated to immune cell killing.
Summary:In these studies, we compared the phenotype, function, and expression of type 1, type 2, and monocyte-associated cytokine mRNA transcripts in autologous bone marrow (BM) and growth factor-mobilized peripheral blood stem cell (PSC) products. These studies demonstrate that lymphocytes and monocytes in stem cell products are abnormally activated, expressing significantly higher levels of interleukin (IL)-2, 4 and 10, interferon gamma (IFN-␥), and tumor necrosis factor alpha (TNF-␣), but not IL-8, as compared to normal peripheral blood mononuclear cells (PBMC). In addition, the levels of IL-2, IL-10 and TNF-␣ are significantly higher in mobilized PSC as compared to BM products. The high cytokine levels are unexpected as T cell function in stem cell products is depressed. PSC products have high levels of T cell inhibitory activity, which directly correlates with IL-10 expression, both of which are mechanisms that might be involved in the immune dysfunction within stem cell products used for autologous stem cell transplantation. These data demonstrate that: (1) immune cells in autologous BM and PSC products are activated with the expression of high levels of type 1 and type 2 cytokines as well as monokines; (2) PSC products contain a high frequency of monocytes which mediate T cell inhibitory activity; and (3) despite the high levels of cytokine expression, T cell function in stem cell products is depressed. The significance of these immune abnormalities within stem cell products for myeloid and lymphoid recovery following autologous stem cell transplantation remains to be determined.
Summary:This study compares the immune properties of peripheral blood stem cell (PSC) products mobilized with different hematopoietic growth factors (HGFs) as well as apheresis products and peripheral blood leukocytes (PBL) from normal individuals. We found that monocytes in mobilized PSC products appear to inhibit T cell function independent of whether granulocyte colonystimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) was used for mobilization. In addition, the GF used to mobilize the stem cell product may be less important to the CD4:CD8 ratio than the extent of prior chemotherapy, as we found an inverse correlation between chemotherapy and the CD4:CD8 ratio. In other observations, all apheresis products, whether mobilized or unmobilized, contained significantly more monocytes compared to normal PBL. The mononuclear cells (MNC) from G-CSF or GM-CSF mobilized PSC products had a similar T cell phytohemagglutinin (PHA) mitogenic response that was significantly lower (P = 0.001 and P = 0.005, respectively) than non-mobilized apheresis products. We also examined the T cell inhibitor (TI) activity of the MNC from the PSC products for allogeneic lymphocyte proliferation and found that PSC products significantly reduced the proliferation of allogeneic PBL to PHA. A significant correlation (P = 0.001, r = 0.517) between the frequency of monocytes and TI activity also was observed.
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