Biomedical subjects
Publications and source records attributed to J P Halper.
Human and murine lymphoid cell populations were induced to express terminal deoxynucleotidyl transferase, a marker of early lymphoid differentiation, by exposure to allogeneic or syngeneic epidermal cells. Control growth medium, fibroblasts, or a mammary epithelial cell line did not induce this marker. These findings suggest that epidermal cells can induce lymphoid cell differentiation in vitro.
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Mononuclear cell suspensions were prepared from 40 normal peripheral blood and lymphoid tissue specimens and 42 neoplastic specimens obtained from patients with malignant lymphoma and lymphocytic leukemia. These suspensions were analyzed for la antigens, surface immunoglobulin (Slg), sheep erythrocyte (E) rosette formation and, in some instances, acid alpha-naphthyl acetate esterase (ANAE) activity. The results of these studies were correlated with the expression of cytochemically demonstrable BG activity. The percentage of BG+ lymphocytes was found to be comparable, within 10%, to the percentage of E+ (T) cells in the majority of normal, non-neoplastic peripheral blood, tonsil, spleen, and lymph node specimens examined. Occasionally, the percentage of E+ cells exceeded the percentage of BG+ cells by 20% or more, suggesting the presence of an E+BG- T cell subpopulation. BG+ B lymphocytes were only demonstrated in 1 of 40 non-neoplastic lymphoid specimens. The neoplastic B cells in each of 14 B cell (la+Slg+E-) lymphomas were BG-. However, a variable proportion of the neoplastic cells isolated from 6 cases of B cell chronic lymphocytic leukemia and neoplastic plasma cells isolated from 7 cases of multiple myeloma expressed BG activity. Thus, it appears that both normal and neoplastic BG- and BG+ B lymphocyte populations exist; the latter may be related to a state of activation or a stage of B cell differentiation. The neoplastic cells isolated from 4 T cell (la-Slg-E+) malignancies were BG+ while those isolated from 3 T cell malignancies were BG-. The variable expression of BG activity by T cell malignancies may be related to T cell differentiation. Investigation of BG expression by T cell derived malignancies may prove useful in sorting out T cell phenotypes.
We correlated the light microscopic features of ten ocular adnexal lymphoid neoplasms with the results of selected immunologic and histochemical lymphocyte marker studies. The lesions were divided into three histomorphologic patterns: inflammatory pseudotumor, reactive follicular hyperplasia, and malignant lymphoma. The six inflammatory pseudotumors, and reactive follicular hyperplasia, despite diverse histomorphology, were immunologically polyclonal and consisted of from 45 to 73% T cells and 27 to 60% B cells, the B cells being polyclonal with respect to light chain determinants. The four malignant lymphomas were immunologically monoclonal. Each consisted of a predominant B-cell proliferation, greater than 50% of the cells, which were monoclonal with respect to surface light chain determinants. No T-cell proliferations were observed. Our preliminary data indicate that, as in systemic lymphoid neoplasms, benign reactive lymphoid hyperplasias are immunologically polyclonal whereas malignant lymphomas are immunologically monoclonal. The systematic application of immunologic and histochemical techniques to the study of ocular adnexal lymphoid neoplasms may elucidate the natural history of these lesions.
The human Ia-like antigens, selectively expressed on B lymphocytes, are now recognized to be closely associated with, or identical to, the gene products of the major histocompatibility complex responsible for stimulation in the mixed lymphocyte reaction. The leukemic B lymphocytes of patients with chronic lymphocytic leukemia express these antigens very well. In the present study they were readily detected by several techniques utilizing both allo- and heteroantisera. However, the leukemic B cells from most patients were found to be extremely poor stimulating cells in the mixed lymphocyte reaction. This was particularly apparent when comparisons were made on a B-cell basis with isolated normal B lymphocytes. Leukemic cell death, abnormal kinetics of leukemic cell-mediated stimulation, and serum or cellular suppressor factors do not appear to explain these findings. Studies comparing cells from a leukemic patient with those of her HLA identical sibling and results of mixed lymphocyte reactions between normal and leukemic subjects discordant for D-region-associated Ia antigens ruled out genetic explanations for the differences observed. Experiments with normal peripheral blood mononuclear cells depleted of T cells and monocytes exclude the quantitative deficiency of monocytes which is found in the peripheral blood of most leukemic patients as an explanation. The present results with chronic lymphocytic leukemia cells indicate that the mere expression of the Ia-like antigens by cell populations does not render them effective stimulators. The accumulated evidence obtained indicate that abnormalities, particularly of membrane function and metabolism, known to occur in chronic lymphocytic leukemia lymphocytes may be involved in the poor stimulatory capacity of the leukemic B cells.
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Previous studies have shown that a distinctive pattern of acid alpha-naphthyl acetate esterase (ANAE) activity (focal reaction product) characterizes normal human peripheral blood and tissue T lymphocytes but is absent from thymocytes and certain mitogen-stimulated T-cell blasts. In the present study mononuclear cell suspensions prepared from the peripheral blood and tissue specimens of 35 patients with lymphoid malignancies were simultaneously analyzed for surface immunoglobulin, sheep erythrocyte rosette formation, Ia antigens, and ANAE activity. The neoplastic cells from 16 patients with Ia+ SIg+ E- (B cell) malignancies, 4 patients with Ia+ SIg- E- (non-B, non-T) acute lymphoblastic leukemia, and 3 patients with Ia- SIg- E- (null cell) malignancies failed to exhibit ANAE activity. The neoplastic cells from 5 patients with Ia- SIg- E+ (T cell-derived) malignancies, including three cutaneous lymphomas, displayed characteristic T-pattern positivity, and in each case the percentage of E+ and ANAE+ cells was comparable. The neoplastic cells from 4 patients with Ia- SIg- E+ (T cell-derived) acute lymphoblastic leukemia were ANAE-. The expression of ANAE activity in T cell-derived malignancies may parallel its expression in the stages of normal T-cell differentiation and may prove to be a useful marker with which to sort out T-cell phenotypes.
Successful induction of in vitro differentiation and immunoglobulin synthesis of the leukemic lymphocytes was carried out in two cases of chronic lymphocytic leukemia. Few plasma cells and little specific Ig secretion were detected in the cultures of isolated leukemic B cells in either the presence or the absence of autologous T cells. Up to 30% of the leukemic B cells matured to plasma cells, and a 32-fold increase in specific Ig synthesis was observed when T cells from normal individuals were added to the cultures of these leukemic B cells. In one of the two cases, autologous T cells were able to induce greater than 50% of the leukemic B cells to differentiate further to plasma cells in the presence of pokeweed mitogen. This markedly accelerated in vitro differentiation was only achieved with leukemic cells from cases in which there was evidence of slight differentiation in vivo. No evidence could be obtained for excessive suppressor T cells in these patients. However, a T-cell defect in the generation of allogeneic effect helper factors was identified. This defect may be responsible for the reduced rate of leukemic maturation in vivo.
Autologous mixed lymphocyte culture (MLC) reactions were studied utilizing autologous purified B cells and autologous established B lymphoid cell lines as stimulating cells. Similar results were obtained although somewhat greater stimulation of lymphocyte proliferation was found with the autologous lymphoid cell lines. Cytotoxic T cells were not generated against the stimulating cells in either case when peripheral blood cells were used as targets. A low cytotoxicity was detected when lymphoid cell lines were used both as stimulators and target cells. However this was nonspecific and was always greater for heterologous lines than for the stimulator line. Third-party cell experiments demonstrated that the autologous reaction could serve as a proliferative stimulus for specific cytotoxic lymphocyte generation. Heat-treated allogeneic lymphocytes that alone do not stimulate proliferation ro cytotoxic T-cell generation in MLC reactions when added to the autologous system produced specific cytotoxic cells. The separation of the proliferative phase from the cytotoxic cell generation was especially striking in these experiments. Possible uses of this system for the generation of specific cytotoxic cells to other nonstimulatory cells are discussed.
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The ultraviolet circular dichroism spectra of human lysozyme are presented. Effects of pH and added inhibitor (N-acetyl-D-glucosamine) were examined and the results were compared with similar measurements of hen egg-white lysozyme. The near-ultraviolet CD spectral bands are substantially different in the human and hen egg-white enzymes. In addition to marked dissimilarities in the spectral interval 260-300 nm, an unusual CD band occurs at an anomalous wavelength (313 nm) in human lysozyme. The pH dependence of the latter suggests a possible interaction, absent in hen egg-white lysozyme, between a tryptophan and a tyrosine residue. Analysis of the spectra furthermore suggests lesser net rotational strengths of tryptophan bands in hen egg-white lysozyme than in human lysozyme, although the latter has one less tryptophan residue. The relationship between the CD spectra and the sequence differences of the proteins is discussed, as well as the CD spectra (published by others) of a closely related protein, bovine alpha-lactalbumin. Contributions of cystine residues to the spectra are examined in the light of possible differences in chirality of one of the four disulfide bridges.The far-ultraviolet CD spectra of human and egg-white lysozyme are quite similar, though not identical. In view of the pronounced differences in side-chain optical activity, and of the effect of pH variation on the far-ultraviolet CD spectrum of human lysozyme, it is likely that at least part of the observed difference in spectra is due to nonpeptide optical activity, and that the proteins have a secondary structure in common.
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