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J H Fitchen

Publications and source records attributed to J H Fitchen.

51 records · Page 3Linked to original sources
PubMed1981

An in vitro model of hematopoietic injury in chronic hypoplastic anemia.

Mice treated with high-dose busulfan develop a 'latent' form of bone marrow failure characterized by near-normal peripheral blood counts and marrow cellularity, but marked reductions in marrow pluripotent stem cells (CFUs) and myeloid progenitor cells (CFUc). Spleen cell suspensions from control and 'latent' mice were placed in liquid culture in the presence of colony-stimulating activity. Cells were harvested at intervals up to 14 days and sub-cultured in agar to assay for CFUc. Baseline splenic CFUc did not differ significantly between control and 'latent' mice. Splenic CFUc from control mice increased 50-fold and reached a peak at day 10 in liquid culture. In contrast, splenic CFUc from 'latent' mice increased only 7-fold and reached a peak at day 3. Our results indicate that although splenic CFUc are present in normal numbers in 'latent' mice, their proliferative capacity is markedly reduced, either as the result of defective CFUc self-renewal or defective feed-in from CFUs or both.

Anemia↗
PubMed1980

Serum inhibitors of myelopoiesis.

A modification of the microcytotoxicity assay of Terasaki & McClelland was used to screen for serum inhibitors of myeloid progenitor cells (CFU-C). Sera from 104 patients with neutropenia or bone marrow failure and from 104 controls, including 30 normal subjects and 74 patients with various disorders or multiple transfusions, were studied. Inhibitors of CFU-C were found in 19 of the 104 patients with neutropenia or marrow failure: three with acquited neutropenia and 16 with aplastic anaemia. In 17 of the 19 patients the inhibitor was either complement dependent or chavincingly associated with clinical remission of disease in one patient. In another patient, the inhibitor was an IgG antibody directed against non-HL1 antigens present on CFU-C of all 50 normal target marrows tested; however, it was not clearly autoreactive. Inhibitors were also found in one of nine patients with lupus erythematosus, one with breast carcinoma, one patient with renal transplant rejection, and six of 46 multiply transfused patients without marrow failure. Our findings indicate that most serum inhibitors are associated with multiple transfusion: convincing evidence of pathogenetically important autoreactive antibody was present in only one of 19 patients with inhibitors.

Adult↗
PubMed1980

Cimetidine and granulopoiesis: bone marrow culture studies in normal man and patients with cimetidine-associated neutropenia.

We studied the effect of the H2-receptor antagonists, cimetidine and metiamide, on in vitro myeloid colony formation by bone marrow cells from seven normal volunteers and two patients with a cimetidine-associated neutropenia. A cimetidine concentration of 500 microgram/ml produced 50% inhibition of normal granulocyte-macrophage colony formation, and 1000 microgram/ml of cimetidine completely suppressed proliferation. The inhibitory effect of metiamide occurred at lower concentrations: 50% inhibition at 250 microgram/ml and 95% inhibition at 350 microgram/ml. Cimetidine had a similar inhibitory effect on colony formation by recovery marrow from the two patients with cimetidine-associated neutropenia. Treatment of autologous and allogeneic marrows with patients' acute phase sera and cimetidine failed to show evidence of antibody-mediated suppression of granulopoiesis. Our results indicate that at sufficiently high concentrations, cimetidine and metiamide inhibit human bone marrow myeloid colony formation in vitro. These findings are consistent with the hypothesis that H2-receptor antagonists may produce neutropenia in a dose-related fashion by injury to granulocytic progenitor cells in vivo.

Adult↗
PubMed1980

Cytotoxicity of anti-beta 2-microglobulin xenoantisera to human and murine myeloid progenitor cells and lack of cross-reactivity with colony-stimulating activity.

A previous report has suggested an antigenic relationship between beta 2-microglobulin (beta 2 mu) and granulocyte colony-stimulating activity (CSA). Since human myeloid progenitor cells (CFU-C) express HLA antigens and beta 2 mu is a known molecular component of HLA antigens, we wondered whether the reported effect of anti-beta 2 mu heteroantisera on in vitro granulopoiesis might result from cytotoxicity to CFU-C rather than from cross-reactivity with CSA. To test this, we used rabbit antibody reactive with human and murine beta 2 mu (anti-beta 2 mu). Treatment of human and murine bone marrow cells with anti-beta 2 mu and complement resulted in 95+% inhibition of CFU-C colony formation compared to controls. To test for an effect on CSA, anti-beta 2 mu was incubated with human and murine sources of CSA. After addition of goat anti-rabbit Ig antiserum to precipitate immune complexes and unbound anti-beta 2 mu, the supernatant fluid retained CSA but was no longer cytotoxic to CFU-C. These results indicate that human and murine CFU-C express membrane beta 2 mu and that anti-beta 2 mu antibody does not cross-react with human or murine CSA.

Animals↗
PubMed1980

Monoclonal antibodies to HLA-A,B, and Ia-like antigens inhibit colony formation by human myeloid progenitor cells.

Hybridomas derived from the fusion of murine myeloma cells with splenocytes from mice immunized with human cultured lymphoid cells secreted monoclonal antibodies to human cell surface antigens. Serologic and immunochemical assays showed that 4 monoclonal antibodies (Ab Q2/47, Q2/61, Q2/70, Q2/80) recognize framework determinants of Ia-like antigens and 1 monoclonal antibody (Ab Q1/28) reacts with determinants expressed on the heavy chain of HLA-A,B antigens. Both anti-HLA-A,B and anti-Ia-like antigen monoclonal antibodies caused complement-dependent inhibition of granulocyte-macrophage colony formation by human bone marrow grown in soft agar. Mixing experiments excluded the possibility of an indirect effect on progenitor cells by lysis of auxiliary cells. These results indicate that human myeloid progenitor cells express HLA-A,B and Ia-like antigens.

Animals↗
PubMed1980

The effect of granulopoietic stress in mice with "latent" bone marrow failure.

We treated mice with high-dose busulfan to produce a residual or "latent" hematopoietic injury characterized by persistent normal or near-normal peripheral blood counts and marrow cellularity but moderate to marked reduction in hematopoietic stem cells. Control and "latent" mice were then challenged with glucan, a granulopoietic stimulant. We found that glucan administration induced a comparable increase in granulocytic differentiation in control and "latent" mice. This differentiational expansion was not accompanied by a further depletion of pluripotent hematopoietic stem cells. Our results fail to demonstrate competition between self-renewal and differentiation at the level of the CFUS, at least in this model. Stimuli for granulopoiesis act primarily on more distal, committed populations which are apparently unaffected by prior exposure to busulfan.

Anemia, Aplastic↗
PubMed1980

[Evidence for CFU-C self-replication (author's transl)].

To explore the proliferative potential of committed myeloid progenitor cells (CFU-C), we placed suspensions of mouse spleen cells in short-term liquid culture with colony stimulating activity and subcultured the cells in agar at intervals to assay for CFU-C. Prior to liquid culture, aliquots of spleen cells were exposed briefly to hypotonic conditions to lyse CFU-S but not CFU-C. A 50-fold increase in CFU-C was observed in control cultures. The pattern of CFU-C proliferation was not altered significantly by hypotonic lysis despite the fact that this treatment effectively removed CFU-S. These results support the hypothesis that CFU-C are capable of self-replication and permit a model of hematopoiesis in which expansion of the granulopoietic pool is controlled, in part, at the level of the CFU-C.

Animals↗
PubMed1979

Phagocytic myeloma cells.

A case of a patient with otherwise typical multiple myeloma whose myeloma cells were phagocytic is described. Phagocytosis of erythrocytes, erythrocytic precursors, lymphocytes, and platelets was found. Ingestion of latex particles by myeloma cells was demonstrated in vitro.

Aged↗
PubMed1979

Antigenic characteristics of normal and malignant human hematopoietic cells. Potential use of antigenic differences in cell separation and marrow transplantation.

Recent studies using cytotoxic and cell separation techniques have identified differentiation-related antigens on human hematopoietic cells. These results, combined with bone marrow transplantation studies, have yielded a picture of antigenic modulation from the pluripotent hematopoietic stem cell through the differentiated end cells.

Antigens, Surface↗
PubMed1979

Human myeloid progenitor cells expressing HLA antigens.

Marrow cells of known HLA type were incubated with HLA antiserum plus complement and then plated in soft agar. Colony formation was consistently inhibited by appropriate HLA antisera. Mixing experiments excluded an indirect effect on CFU-C by lysis of mature leukocytes. We conclude that human CFU-C express HLA antigens.

Antibody Specificity↗
PubMed1978

Pretransplant lymphocytotoxins and bone-marrow graft rejection.

A correlation was demonstrated between bone-marrow graft rejection and pretransplant lymphocytotoxins. This finding might prove useful as a test for identification of patients at high risk of rejection who might benefit from more intensive immunosuppression.

Adolescent↗
PubMed1978

Recent developments in understanding the pathogenesis of aplastic anemia.

Bone marrow failure in aplastic anemia (AA) could result from abnormalities of hematopoietic stem cells, abnormal control of hematopoiesis, or abnormalities of the hematopoietic environment. Bone marrow transplantation, in vitro marrow culture techniques, and studies in animal models of marrow failure have provided insights on the possible pathogenetic mechanisms underlying AA. Studies in man and in murine models suggest that most often AA results from injuries to hematopoietic stem cells. Despite the intriguing report of abnormal regulatory cells in congenitally anemic mice, instances of marrow failure due to defective humoral or cellular control of hematopoiesis have not been identified in man. In vitro studies employing allogeneic marrow targets have suggested that immune suppression of hematopoiesis may occasionally mediate AA in man. Marrow failure due to abnormalities of the hematopoietic microenvironment has been suggested by experience with bone marrow transplantation, but no direct study of this possibility has been reported. Based on available evidence, it seems likely that AA will prove to be many diseases that share common clinical and morphologic features.

Anemia, Aplastic↗