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PubMed2005

[In vitro evidence for pancreatic lineage: Ngn3 positive cells are endocrine progenitors derived from cultured islets].

OBJECTIVE: Further studies have been conducted to evaluate the roles of Ngn3 in adult islet maintenance and renewal. METHODS: Islets were isolated from 6 - 8 week old male C57BL/6 mice. After common bile duct cannulation, the pancreas was resected and digested in collagenase V (2.5 mg/ml). Islets were then handpicked and 10 - 12 islets were plated in 60 mm culture dish and cultivated with RPMI-1640, which contained 12.5 mmol/L HEPES, 5.2 mmol/L glucose and 2% fetal bovine serum (FBS). Islet cells were analyzed by immunocytochemistry methods for A6, insulin, glucagon, nestin, Ngn3 and 5-bromo-2'-deoxy-uridine (BrdU). RESULTS: The results of these studies indicated that less than 15 percent of proliferated islet cells were Ngn3 expressing cells, in which about one third of the Ngn3 positive cells co-expressed A6. The existence of Ngn3 in cultured islet cells is consistent with the results from other's findings both in embryogenesis and adult islet studies. A significant finding of our study is that the existence of A6 and Ngn3 co-expressing cells in the cultured islet. A6 is a marker for identifying bile duct epithelial cell oriented hepatic progenitor cells. Islet-derived A6 cells are possibly born in the adult pancreatic duct and migrate into islets. A6 cells co-express Ngn3 when these cells commit to endocrine lineage within the islets. More interestingly, islet-derived A6 positive cells have the potential to transdifferentiate into hepatic cells. CONCLUSION: The presence of Ngn3(+) and A6(+) cells in the cultured islets suggests that the four established islet cell types arise from a common endocrine lineage residing within the adult islets. A6 and Ngn3 are useful markers for understanding intra-islet adult stem cell lineages in our future studies. This approach may allow for significant advances in understanding the IPC proliferation and differentiation, and open the possibility of using intra-islet adult stem cells for diabetes treatment.

Animals↗

PubMed1996

Rabbit conjunctival and corneal epithelial cells belong to two separate lineages.

PURPOSE: This study investigated rabbit conjunctival and corneal epithelial cells to determine if they belong to two separate lineages. METHODS: Rabbit corneal, limbal, and conjunctival epithelial cells were isolated and grown in Dulbecco's minimum essential media and 20% fetal bovine serum in the presence of mitomycin-treated 3T3 feeder cells. After reaching 80% confluence, 3T3 feeder cells and any contaminating fibroblasts were removed, and epithelial cells were resuspended in fresh Dulbecco's minimum essential media. Aliquots containing 5x10(6) cells were placed subcutaneously into the flanks of athymic mice, which subsequently formed small nodules. At 2, 4, 6, 8, 14, 21, and 28 days, athymic mice were killed and the nodules (epithelial cyst) were excised for light and transmission electron microscopic examination and histochemical and cell kinetic analyses. RESULTS: Within 2 days after injection of single-cell suspensions, cells aggregated to form cysts lined with a stratified squamous epithelium, the structure of which resembled the original in vivo donor sites by 8 days. Limbal- and corneal-derived cysts were comprised only of glycogen-rich stratified epithelial cells. In contrast, only cysts arising from cultured conjunctival cells contained periodic acid-Schiff-positive cells with a goblet cell structure interspersed among stratified epithelial cells. Furthermore, cystic epithelium of conjunctival origin did not accumulate glycogen. CONCLUSIONS: To determine whether distinct phenotypes are caused by intrinsic divergence or by environmental modulation, the behavior of cells can be monitored in an identical in vivo growth environment. The athymic mouse provides such a permissive growth environment for cultured corneal, limbal, and conjunctival epithelial cells. All these cells reproduced their in vivo phenotype when placed in the athymic mouse. Thus, these findings provide the strongest evidence to date that the corneal-limbal lineage is distinct from the conjunctival lineage. These data also support the idea that the progenitor of goblet cells does not reside in the corneal-limbal epithelial compartment.

Animals↗

PubMed1997

Lineage-specific regulation of hematopoiesis by HOX-B8 (HOX-2.4): inhibition of granulocytic differentiation and potentiation of monocytic differentiation.

Homeobox proteins comprise a major class of transcription factors, which have been implicated in normal hematopoiesis and leukemogenesis. Notable in this context is the homeobox gene HOX-B8 (formerly known as HOX-2.4), which was shown to cooperate with hematokines to induce leukemia, and to enhance self-renewal of immature myeloid progenitors when expressed alone. How HOX-B8 may affect lineage specific development of hematopoietic progenitor cells is unknown. Here it is shown that ectopic expression of HOX-B8 specifically inhibited dimethyl sulfoxide (DMSO)-induced granulocytic differentiation of autonomously proliferating HL-60 myeloid progenitor cells. HOX-B8 also inhibited the granulocyte colony-stimulating factor (G-CSF)-induced granulocytic developmental program of factor dependent 32Dcl3 hematopoietic progenitors, including survival, proliferation, and differentiation, as evident by rapid apoptosis of the cells following removal of interleukin-3 (IL-3) and addition of G-CSF. In sharp contrast, HOX-B8 had no effect on macrophage differentiation of M1 and HL-60 cells induced by IL-6 and phorbol-12-myristate-13-acetate, respectively. Moreover, HOX-B8 expression endowed the 32Dcl3 cells with the ability to be induced by granulocyte-macrophage colony-stimulating factor (GM-CSF) for terminal differentiation exclusively along the macrophage lineage; this effect was at least partially mediated via expression of the zinc finger transcription factor Egr-1. Thus, ectopic expression of HOX-B8 in hematopoietic progenitor cells appears to differentially affect lineage specific development, negatively regulating granulocyte development and positively regulating macrophage development.

Animals↗

PubMed1997

PU.1/Pip and basic helix loop helix zipper transcription factors interact with binding sites in the CD20 promoter to help confer lineage- and stage-specific expression of CD20 in B lymphocytes.

CD20 is a B-lineage-specific gene expressed at the pre-B-cell stage of B-cell development that disappears on differentiation to plasma cells. As such, it serves as an excellent paradigm for the study of lineage and developmental stage-specific gene expression. Using in vivo footprinting we identified two sites in the promoter at -45 and -160 that were occupied only in CD20+ B cells. The -45 site is an E box that binds basic helix-loop-helix-zipper proteins whereas the -160 site is a composite PU.1 and Pip binding site. Transfection studies with reporter constructs and various expression vectors verified the importance of these sites. The composite PU.1 and Pip site likely accounts for both lineage and stage-specific expression of CD20 whereas the CD20 E box binding proteins enhance overall promoter activity and may link the promoter to a distant enhancer.

Antigens, CD20↗

PubMed1998

The alpha-chemokine receptor CXCR4 is expressed on the megakaryocytic lineage from progenitor to platelets and modulates migration and adhesion.

CXCR4 is the receptor for the alpha-chemokine stromal cell-derived factor 1 (SDF-1) and has been shown to be expressed on a diversity of leukocytes. In this report, the expression of the CXCR4 receptor in cells of megakaryocytic lineage and the role of SDF-1 in megakaryocytopoiesis were investigated. Using flow cytometry in combination with reverse transcriptase-polymerase chain reaction (RT-PCR), we observed that bone marrow CD34(+), CD61(+) cells, blood platelets, and megakaryocytic leukemia cell lines all expressed the CXCR4 receptor. To examine the expression of the CXCR4 receptor on megakaryocyte progenitors (colony-forming units-megakaryocyte [CFU-Meg]), CXCR4-positive and -negative CD34(+) populations were separated from bone marrow and cultured in a plasma clot culture system. A subpopulation of the CFU-Meg was found in the CXCR4-positive fraction. The functional significance of CXCR4 expression on cells of the megakaryocytic lineage was examined by studying the effects of SDF-1alpha on migration and proliferation of megakaryocyte progenitor cells in vitro. We found that SDF-1alpha potently induced megakaryocyte progenitor migration and significantly enhanced adhesion of mature marrow megakaryocytes to endothelium. No marked effects of SDF-1alpha alone or in combination with thrombopoietin and stem cell factor/kit ligand on megakaryocyte production in vitro were noted. These results demonstrate for the first time that the CXCR4 alpha-chemokine receptor is expressed on cells of the megakaryocytic lineage from progenitors to platelets and that its ligand SDF-1alpha may modulate several aspects of megakaryocytopoiesis.

Antigens, CD34↗

PubMed1998

Flow cytometric diagnosis of the cell lineage and developmental stage of acute lymphoblastic leukemia by novel monoclonal antibodies specific to human pre-B-cell receptor.

Three novel monoclonal antibodies (MoAbs) have been established that recognize distinct epitopes of a human pre-B-cell receptor (pre-BCR) composed of a mu heavy (muH) chain and a lambda5/VpreB surrogate light (SL) chain. HSL11 reacts with lambda5 whereas HSL96 reacts with VpreB. Intriguingly, HSL2 does not bind to each component of the pre-BCR but does bind to the completely assembled pre-BCR complex. Flow cytometric analyses with cytoplasmic staining of a panel of human cell lines showed that HSL11 and HSL96 specifically stained cell lines derived from the pro-B and pre-B-cell stages of B-cell development. In contrast, HSL2 stained exclusively cell lines derived from the pre-B-cell stage. These results prompted us to explore the possibility of clinical application of these MoAbs for the determination of the cell lineage and developmental stage of acute lymphoblastic leukemia (ALL). Whereas none of mature B-lineage ALLs (B-ALLs), T-lineage ALLs (T-ALLs), and acute myeloid leukemias analyzed were stained in the cytoplasm with these three MoAbs, the vast majority of non-B- and non-T-ALLs (53 out of 56 cases) were found positive for either lambda5, Vpre-B, or both in their cytoplasm. Among these 53 cytoplasmic SL chain-positive ALLs, 19 cases were also positive for cytoplasmic muH chain, indicative of pre-B-cell origin. Interestingly, 6 out of these 19 pre-B-ALL cases were found negative for cytoplasmic staining with HSL2. From these results, we propose a novel classification of B-ALL in which five subtypes are defined on the basis of the differential expression of SL chain, muH chain, pre-BCR, and light chain along the B-cell development.

Antibodies, Monoclonal↗

PubMed1998

MUC1 is a novel marker for the type II pneumocyte lineage during lung carcinogenesis.

Abnormalities in mucin-type glycoprotein expression have been documented in a variety of cancers, identifying these molecules as targets for immunologically based therapies and prognostic/diagnostic assays. We examined the expression of the membrane-bound MUC1 mucin in normal, histologically atypical, and neoplastic lung to determine its potential contribution to lung carcinogenesis. In vivo, intense MUC1 immunoreactivity was present in normal type II pneumocytes as well as in a range of atypical lesions derived from type II cells and >60% of primary and metastatic non-small cell lung cancers. Expression was not associated with altered survival, although it was highly correlated with the adenocarcinoma histology. A carcinogenesis model using 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone-exposed hamsters revealed that MUC1 mRNA increased prior to the histological appearance of tumors. In vitro studies using MUC1 expressing non-small cell lung cancer cell lines revealed that differentiation away from a type II cell lineage was associated with dramatic down-regulation of MUC1. We propose that MUC1 is a powerful new marker for the type II pneumocyte cell lineage that allows us to follow the type II pneumocyte lineage during the process of lung carcinogenesis.

Animals↗

PubMed1999

Lineage-restricted expression of protein kinase C isoforms in hematopoiesis.

The pattern of expression of several protein kinase C (PKC) isoforms (alpha, betaI, delta, epsilon, eta, and zeta) during the course of hematopoietic development was investigated using primary human CD34(+) hematopoietic cells and stable cell lines subcloned from the growth factor-dependent 32D murine hematopoietic cell line. Each 32D cell clone shows the phenotype and growth factor dependence characteristics of the corresponding hematopoietic lineage. Clear-cut differences were noticed between erythroid and nonerythroid lineages. (1) The functional inhibition of PKC-epsilon in primary human CD34(+) hematopoietic cells resulted in a twofold increase in the number of erythroid colonies. (2) Erythroid 32D Epo1 cells showed a lower level of bulk PKC catalytic activity, lacked the expression of epsilon and eta PKC isoforms, and showed a weak or absent upregulation of the remaining isoforms, except betaI, upon readdition of Epo to growth factor-starved cells. (3) 32D, 32D GM1, and 32D G1 cell lines with mast cell, granulo-macrophagic, and granulocytic phenotype, respectively, expressed all the PKC isoforms investigated, but showed distinct responses to growth factor readdition. (4) 32D Epo 1.1, a clone selected for interleukin-3 (IL-3) responsiveness from 32D Epo1, expressed the epsilon isoform only when cultured with IL-3. On the other hand, when cultured in Epo, 32D Epo1.1 cells lacked the expression of both epsilon and eta PKC isoforms, similarly to 32D Epo1. (5) All 32D cell lines expressed the mRNA for PKC-epsilon, indicating that the downmodulation of the epsilon isoform occurred at a posttranscriptional level. In conclusion, the PKC isoform expression during hematopoiesis appears to be lineage-specific and, at least partially, related to the growth factor response.

Animals↗

PubMed2000

Georgian and kurd mtDNA sequence analysis shows a lack of correlation between languages and female genetic lineages.

Mitochondrial DNA sequences from Georgians and Kurds were analyzed in order to test the possible correlation between female lineages and languages in these two neighboring West Eurasian groups. Mitochondrial sequence pools in both populations are very similar despite their different linguistic and prehistoric backgrounds. Both populations present mtDNA lineages that clearly belong to the European gene pool, as shown by 1) similar nucleotide and sequence diversities; 2) a large number of sequences shared with the rest of European samples; 3) nonsignificant genetic distances; and 4) classification of the present lineages into the major European mtDNA haplogroups already described. The outlier position of the populations from the Caucasus according to classical genetic markers is not recognized in the present Georgian mtDNA sequence pool. This result suggests that the differentiation of mtDNA sequences in West Eurasia and the outlier features of Caucasian populations should be attributed to different processes. Moreover, the putative linguistic relationship between Caucasian groups and the Basques, another outlier population within Europe for classical genetic markers, is not detected by the analysis of mtDNA sequences.

Adult↗

PubMed1999

Protein kinase C activity regulates slow myosin heavy chain 2 gene expression in slow lineage skeletal muscle fibers.

Expression of the slow myosin heavy chain (MyHC) 2 gene defines slow versus fast avian skeletal muscle fiber types. Fetal, or secondary, skeletal muscle fibers express slow MyHC isoform genes in developmentally regulated patterns within the embryo, and this patterning is at least partly dependent on innervation in vivo. We have previously shown that slow MyHC 2 gene expression in vitro is regulated by a combination of innervation and cell lineage. This pattern of gene expression was indistinguishable from the pattern observed in vivo in that it was restricted to innervated muscle fibers of slow muscle origin. We show here that slow MyHC 2 gene expression in the slow muscle fiber lineage is regulated by protein kinase C (PKC) activity. Inhibition of PKC activity induced slow MyHC 2 gene expression, and the capacity to express the slow MyHC 2 gene was restricted to muscle fibers of slow muscle (medial adductor) origin. Fast muscle fibers derived from the pectoralis major did not express significant levels of slow MyHC 2 with or without inhibitors of PKC activity. This differential expression pattern coincided with different inherent PKC activities in fast versus slow muscle fiber types. Furthermore, over-expression of an unregulated PKCalpha mutant suppressed slow MyHC 2 gene expression in muscle fibers of the slow lineage. Lastly, denervation of skeletal muscles caused an increase in PKC activity, particularly in the slow medial adductor muscle. This increase in PKC activity was associated with lack of slow MyHC 2 gene expression in vivo. These results provide a mechanistic link between innervation, an intracellular signaling pathway mediated by PKC, and expression of a muscle fiber type-specific contractile protein gene. Dev Dyn 1999;216:177-189.

Animals↗

PubMed1997

Nasal T/natural killer (NK)-cell lymphomas are derived from Epstein-Barr virus-infected cytotoxic lymphocytes of both NK- and T-cell lineage.

The cellular nature of nasal T/natural killer (NK)-cell lymphomas (NLs) remains controversial. It is still debatable whether these represent T-cell lymphomas with extensive loss of surface antigens or are, in fact, true NK-cell lymphomas. They are associated closely with Epstein-Barr virus (EBV), to the extent that EBV-encoded small non-polyadenylated RNAs (EBER) expression can be used as a marker for the neoplastic cells. The cell lineage of this group of lymphomas was examined further by correlating immunophenotype, genotype and EBV status with the expression of cytotoxic granule-associated proteins, perforin and T-cell intracellular antigen-1 (TIA-1) in 13 cases of NL. Combined immunophenotypic and gene rearrangement analyses demonstrated that NLs can be identified clearly as either NK-cell or T-cell tumours. Nasal NK-cell lymphomas lacked clonal rearrangement of both T-cell receptor (TCR) gamma and immunogloulin heavy chain (IgH) genes and were either CD3(Leu4)-CD56+ (8 cases) or CD3(Leu4)+CD56+ (2 cases), whereas nasal T-cell lymphomas had rearranged TCRgamma and germ-line IgH genes and were either CD3(Leu4)+CD56+ (2 cases) or CD3(Leu4)+CD56- (1 case). Immunohistochemical (IH) studies showed that both perforin and TIA-1 were expressed universally in NL, irrespective of NK- or T-cell lineage. Dual labelling of TIA-1 by IH and EBER by in situ hybridisation demonstrated that the granule proteins were expressed predominantly by the EBER+ tumour cells. Our results indicate that NLs are derived from EBV-infected cytotoxic lymphocytes of both NK- and T-cell lineage. We postulate that cytotoxic lymphocytes generated during the cellular immune response to EBV infection or re-activation at the nasal region themselves may become targets for EBV infection and subsequent transformation.

Gene Rearrangement, B-Lymphocyte, Heavy Chain↗

PubMed1997

Structure and function analysis of the human myeloid cell nuclear differentiation antigen promoter: evidence for the role of Sp1 and not of c-Myb or PU.1 in myelomonocytic lineage-specific expression.

The human myeloid nuclear differentiation antigen (MNDA) is expressed specifically in maturing cells of the myelomonocytic lineage and in monocytes and granulocytes. Epitope enhancement was used to confirm the strict lineage- and stage-specific expression of MNDA in bone marrow as well as in other paraffin-embedded fixed tissues. A 1-kb region of the gene that includes 5' flanking sequence was reported earlier to contain functional promoter activity and was specifically demethylated in expressing cells in contrast to null cells. Further analysis has revealed that this 1-kb fragment promotes higher reporter gene activity in MNDA-expressing cells than non-expressing cells, indicating cell-specific differences in transactivation. This sequence contains consensus elements consistent with myeloid-specific gene expression, including a PU.1 consensus site near the major transcription start site and a cluster of c-Myb sites located several hundred bases upstream of this region. However, analysis of deletion mutants localized nearly all of the promoter activity to a short region (-73 to -16) that did not include the cluster of c-Myb sites. A 4-bp mutation of the core Sp1 consensus element (GC box) (-20) reduced overall promoter activity of the 1-kb fragment. Mutation of the PU.1 site did not significantly affect promoter activity. Only a small region (-35 to +22) including the Sp1 element and transcription start site, but not the PU.1 site was footprinted. The 4-bp mutation of the core Sp1 consensus element abolished footprinting at the site and an antibody super-shift reaction showed that Sp1 is one of the factors binding the consensus site. The Sp1 site also co-localizes with a DNase I hypersensitive site. The results indicate that DNA methylation, chromatin structure, and transactivation at an Sp1 site contribute to the highly restricted expression of this myelomonocytic lineage specific gene.

Antigens, Differentiation, Myelomonocytic↗

PubMed1999

Metanephric rat-mouse chimeras to study cell lineage of the nephron.

The nephron is derived from the ureteric bud and metanephric mesenchyme and develops into a complex epithelial structure with a wide variety of phenotypes along its length. This segmental variation in expression of molecules provides an approach to understand the lineage of unique segments. The present study evaluated the expression of four relatively well-localized molecules--renin, Tamm-Horsfall protein (THP), oxytocin receptor (OTR), and the vasopressin type 2 receptor (V2R)--in cultured mouse-rat chimeric metanephric kidneys using reverse transcription-polymerase chain reaction (RT-PCR). Chimeric kidneys were formed by 1) separating the ureteric bud (U) from the metanephric mesenchyme (M) of mouse (m) at E11 and rat (r) at E13 days of gestation and 2) recombining the ureteric bud of one species with the metanephric mesenchyme of the other species (i.e., UrMm and UmM(r), followed by filter culture until differentiated. Species-specific restriction enzymes for all four genes were chosen to digest the PCR product from either rat or mouse. RT-PCR was performed for each mRNA species and the products digested. The V2R product from the UrMm chimera was cleaved by a restriction enzyme known to digest only rat product, suggesting the PCR product was produced predominantly by cells derived from the ureteric bud. The renin, OTR, and THP products from both chimeras were cleaved equally well by species-specific restriction enzymes, suggesting the products were made by cells originating from both the ureteric bud and the metanephric mesenchyme. These studies demonstrate that the cultured chimeric metanephric model is useful to study segment lineage. The results suggest that the lineage of at least certain portions of the nephron is heterogenous.

Animals↗

PubMed1989

Immunophenotyping in the classification of acute leukemia in adults. Interpretation of multiple lineage reactivity.

Fifty-nine adult patients with acute leukemia were classified using a combination of the French-American-British (FAB) criteria and characterization by immunophenotyping using flow cytometric study. The authors identified 51 patients with acute myeloblastic leukemia and eight with acute lymphoblastic leukemia. This procedure permitted lineage assignment in leukemias that otherwise might have been unclassifiable. In addition, the authors demonstrated that the leukemic blasts of 29% of patients with myeloblastic disease exhibited one or more T-cell antigens on their surface. The use of immunophenotyping has greatly enhanced the authors' ability to correctly identify the lineage of acute leukemias. The data, however, must be interpreted with caution with respect to diagnosing acute mixed lineage leukemias and must be integrated with the morphologic and cytochemical evaluation of traditional classification schemes. The possible significance of T-cell markers in myeloblastic leukemia is discussed.

Adult↗

PubMed2000

Lysenin-sphingomyelin binding at the surface of oligodendrocyte lineage cells increases during differentiation in vitro.

We have investigated the relationship between the developmental expression of sphingomyelin, a major component of myelin, and oligodendrocyte lineage. Using lysenin as a cytochemical probe for membrane sphingomyelin, we have now determined the distribution pattern of sphingomyelin on the plasma membrane of rat cultured oligodendrocytes. Although lysenin does not bind to A2B5(+)/NG2(+) bipolar oligodendrocyte progenitors, lysenin recognizes sphingomyelin on the cell bodies of multipolar A2B5(+) cells, but not on their processes. O4(+) and O1(+) immature and MBP(+) mature oligodendrocytes are strongly labeled by lysenin from cell bodies to the tips of processes. The content of sphingomyelin in immature and mature oligodendrocytes is approximately 2-fold higher than that in oligodendrocyte progenitors. These findings show that sphingomyelin increases during differentiation of cells in the oligodendrocyte lineage. In multipolar oligodendrocyte progenitors exposed to Triton X-100 at 4 degrees C, lysenin labels cell processes in addition to cell bodies. In contrast, Triton X-100 extraction does not alter the distribution of lysenin binding on O4(+), O1(+) and MBP(+) cells, although the immunocytochemical intensities of the lysenin bindings increase. Our data suggest that the alteration in sphingomyelin content and distribution in the oligodendrocyte lineage cells could have important consequences for cell recognition and downstream signaling events through sphingomyelin-rich domains.

Animals↗

PubMed2000

Low expression level but potent antigen presenting function of CD1d on monocyte lineage cells.

CD1d is a key antigen-presenting molecule involved in the selection and activation of a highly conserved T cell subset known as NK T cells. In this study, we analyzed the expression, regulation and function of human CD1d by various antigen-presenting cells (APC) of myeloid origin, including circulating monocytes, monocyte-derived dendritic cells and macrophages. CD1d was expressed as a mature glycoprotein by these cells, and unlike the other members of the human CD1 family its expression was constitutive and was not strongly up-regulated by GM-CSF and IL-4 or a range of other cytokines. Despite their remarkably low surface expression of CD1d, all myeloid lineage cells tested were extremely potent APC for responses of NK T cell clones to the synthetic glycolipid antigen, alpha-galactosyl ceramide. Prominent localization of CD1d to the endocytic system of monocyte lineage cells was observed, and functional studies suggested that this was important for achieving efficient antigen loading onto CD1d. Overall, these results support the view that monocyte lineage cells are important stimulators of CD1d-restricted immune responses, while also underscoring the unique regulation of CD1d expression by these cells.

Antibodies, Monoclonal↗

PubMed1984

Life history of cells mediating natural resistance to tumor cells and bone-marrow transplants: the respective roles of cell lineage commitment and host environment in determining strain characteristics of natural resistance to foreign marrow grafts.

A class of cells present in the blood and lymphoid tissues of mammals produces rapid cytolysis of tumor cells on first contact. Abundant evidence suggests that such natural killer (NK) cells play a role in tumor immunosurveillance in vivo. A similarly prompt and spontaneous activity can cause the rejection of foreign marrow transplants. These phenomena are known collectively as natural resistance. The cells mediating natural resistance are lymphoid in morphology, but are neither T nor B lymphocytes. Kinetically, NK cells and cells mediating natural resistance to foreign marrow grafts are themselves nondividing but are rapidly renewed from radiosensitive proliferating precursors in the bone marrow. They appear to have no long-lived (memory) component. Newly formed NK cells have a short residence time in the spleen. Other general properties of the natural-resistance cell lineage, including strain variation, ontogeny, and cell phenotype, are reviewed in this article. The present study aimed to examine the respective roles of cell lineage commitment and of the host environment in determining strain characteristics of natural resistance to foreign marrow grafts. Chimeras produced by inoculating mice of a strain that normally has little or no natural resistance with bone marrow from adult mice of a highly resistant strain develop resistance to a third-party marrow allograft. Such chimeras do not develop the full rejection capacity of the high-resistance strain, however; and chimeras created by inoculating marrow from infant mice develop less resistance than those reconstituted by bone marrow from adult mice. The results demonstrate that the ability to reject foreign marrow grafts develops as an intrinsic property of the natural-resistance cell lineage. The host environment may provide an additional influence, however, particularly in the initial development of natural resistance in early postnatal life.

Animals↗

PubMed1991

Transitions in CD45 isoform expression indicate continuous differentiation of a monoclonal CD5+ CD11b+ B lineage in Waldenstrom's macroglobulinemia.

Waldenstrom's macroglobulinemia (WM) has been hypothesized to be a pleomorphic B-cell malignancy with persistent maturation towards plasma cells in all lymphoid tissue. This proposal is based on detection of a heterogeneous density of monoclonal Ig on peripheral blood B-cells in patients with WM. We now present data derived from 2- and 3-color immunofluorescence and flow cytometric analysis that strongly supports this hypothesis. Abnormally high numbers of B lineage cells, defined by expression of CD19, CD20, and CD24, were found among peripheral blood mononuclear cells (PBMC). These B-cells are monoclonal as defined by light chain expression and by the existence of rearranged Ig genes (Southern blot analysis), although they exhibit heterogeneity in the density of surface light chain. Unlike normal PBMC B-cells, the monoclonal B-cells bear CD5 and CD10 (CALLA), express adhesion and adhesion-related molecules (CD11b, CD9), and appear to be actively differentiating during the course of the disease, based on the pattern of CD45 isoform expression. At any given point in time, the population of monoclonal B-cells is heterogeneous in differentiation stage based on transitions in the expression of CD45 isoforms from expression of CD45RA, the high molecular mass isoforms of CD45, to the low molecular mass isoform CD45R0 which appears only on very late stage B-cells and early plasma cells. For one patient, analysis of CD45 isoform expression over 2 years showed that the monoclonal B-cell population as a whole progressed towards terminal differentiation as defined by loss of CD45RA and acquisition of CD45R0. This indicates a continuously differentiating lineage of an unusual B-cell phenotype, and/or malignant transformation of a distinct lineage of B-cells in WM.

Antigens, CD↗