Human T-cell leukemia/lymphoma virus: studies of host-virus interaction.
Explore the source record for details and available documents.
Antibodies, Monoclonal↗
Biomedical subjects
B F Haynes
Publications and source records attributed to B F Haynes.
In vitro growth and phenotypic characterization of mesodermal-derived and epithelial components of normal and abnormal human thymus.
Long-term in vitro cultures of human thymic tissue were established and phenotypically characterized using monoclonal reagents that define distinct components of the human thymic microenvironment. The epithelial component of the thymus, defined by monoclonal antibodies TE-3, TE-4, BBTECS, and AE1 (anti-keratin) was isolated from the mesodermal component, defined by antibody TE-7, and maintained separately in long-term culture. The epithelial cells were subcultured repeatedly and recovered from storage in liquid nitrogen. The in vitro phenotype of the cultured cells was compared to that of cultured human epidermal cells. A subpopulation of cultured thymic epithelial cells along with a subpopulation of cultured epidermal cells expressed antigens (TE-8, TE-15) characteristic of late stages of keratinized epithelial cell differentiation. Thus, we have established a system whereby components of the human thymic microenvironment can be cultivated in vitro while maintaining the capacity to differentiate. This approach can be used to evaluate the role of components of the thymic microenvironment at various stages of differentiation on developing T lymphocytes. In addition, keratin-containing thymic epithelial cells were successfully cultured from thymuses obtained from patients with myasthenia gravis and thymoma. Cultivation of abnormal thymic epithelium will provide insight into aberrant T lymphocyte-thymic epithelial interaction.
Adolescent↗
Expression of antigens by cultured epithelial cells: comparison of epidermis and thymic epithelium.
We have established long term in vitro cultures of human thymic epithelium and human epidermis free of contaminating fibroblasts. The cultured cells were examined using a panel of monoclonal antibodies which were raised against human thymic stroma and recognize tissue specific differentiation antigens of human epidermis and thymic epithelium. A subset of cultured epidermal cells (50%) and thymic epithelial cells (18%) expressed the TE-4 antigen characteristic of basal keratinocytes in skin and endocrine epithelium found in the subcapsular cortex and medulla of the thymus. Subpopulations of the cultured cells expressed the antigens detected by antibodies TE-8 and TE-15. In tissue sections antibodies TE-8 and TE-15 bound to the stratum granulosum and stratum corneum of skin and to the Hassall's bodies of thymus, and therefore recognize antigens characteristic of late stages of keratinized epithelial differentiation. In addition, a subset of thymic epithelial cells expressed the antigen detected by antibody TE-3 which is expressed by nonendocrine thymic epithelium found in the thymic cortex. Thus, in vitro cultures of both epidermal and thymic epithelial cells expressed the entire array of differentiation antigens detected by our panel of monoclonal antibodies. This approach can be used to evaluate the role of components of the thymic microenvironment at various stages of differentiation on developing T lymphocytes. In addition, the cultured epidermal cells can be used to evaluate epidermis as a site of extrathymic T cell maturation.
Adolescent↗
Antibody against T lymphoblastic leukemia-associated antigen (3-40) identifies vimentin and keratin intermediate filaments in normal cells.
Antibody 3-40 defines a 35- to 40-kd surface antigen present on T lymphoblastic leukemia (T-ALL) cells that is absent on normal hematopoietic cells (Naito et al, Blood 62:852, 1983). Using immunoblot analysis of cytoskeletal proteins and indirect immunofluorescence of cell lines treated with various cytoskeletal inhibitors, in this report we have demonstrated that antibody 3-40 also identifies vimentin intermediate filaments (IMF) within the HSB-2 (T-ALL) cell line as well as in normal thymocytes, peripheral blood mononuclear cells, and human and rodent fibroblast cell lines. Cross-reactivity with several keratin subclasses was demonstrated in both human and rodent epithelial cell lines, human thymus, and skin. In addition, we have shown that antibody 3-40 defined a 39-kd intracellular IMF-associated protein in HSB-2 cells, epithelial and fibroblast cell lines. This IMF-associated protein may be selectively expressed on the surface of human T cells during malignant transformation.
Animals↗
The human thymic microenvironment. Phenotypic characterization of Hassall's bodies with the use of monoclonal antibodies.
The human thymic microenvironment is important in promotion of T cell maturation, particularly during early stages of thymic ontogeny. Hassall's bodies (HB) are epithelial swirls in the human thymic medulla that are thought to be derived from endocrine medullary thymic epithelium. To study the ontogeny and function of various components of the human thymic microenvironment, we have produced four monoclonal antibodies (TE-8, TE-15, TE-16, and TE-19) that selectively reacted in thymus with HB. Antibodies TE-8 and TE-16 reacted with the cells forming the outer rim of the HB swirl. Antibody TE-19 reacted with the entire cellular portion of HB and with epithelial cells immediately surrounding HB. Granular foci in the cellular swirls of greater than 90% of HB reacted with antibody TE-15. During thymic ontogeny, the antigens defined by antibodies TE-8, TE-15, TE-16, and TE-19 were first detected in fetal thymus on HB beginning at 16 wk gestation, the age when HB morphologically appear in the thymus. Aberrant expression of the antigens corresponding to antibodies TE-8, TE-15, TE-16, and TE-19 was observed on thymic tissue from individuals with severe cellular immunodeficiency disease. In human skin, antibodies TE-8, TE-16, and TE-19 reacted with the stratum granulosum; antibody TE-15 reacted with the stratum corneum. Thus, with the use of antibodies TE-8, TE-15, TE-16, and TE-19, we have identified HB as antigenically distinct regions of endocrine thymic epithelium. Furthermore, we have shown that these anti-HB reagents also selectively react with epidermal keratinocytes in the terminal stages of keratinocyte maturation.
Animals↗
Monoclonal antibodies reactive with human T cell lymphotropic virusI (HTLVI) p19 internal core protein: cross-reactivity with normal tissues and differential reactivity with HTLV types I and II.
Three monoclonal antibodies to human T cell lymphotropic virus type I (HTLVI) p19 internal core protein, designated as alpha HTLV-2, 3, and 4, have been developed. In indirect immunofluorescence (IF) assays, these antibodies reacted with acetone-fixed cytocentrifuge preparations of culture HTLVI-infected peripheral blood leukocyte (PBL) from a patient (SD) with Japanese adult T cell leukemia and with infected HUT-102 T cells but not with cultured normal PBL. Anti-p19 antibodies alpha HTLV-2, 3, and 4 all reacted with the same HTLVI p19 identified both by antibodies in HTLVI+ patient sera and by antisera raised against two synthetic peptides encoded by the p19 gag region of HTLVI. Partial proteolytic cleavage of p19 immunoprecipitates obtained with antibodies alpha HTLV-2, 3, and 4 produced a 17,000-dalton cleavage product, in agreement with the size of the fragment predicted from the nucleic acid sequence of the HTLVI p19 gag region. Antibodies alpha HTLV-3 and 4 reacted with HTLVI but not HTLVII proteins and were useful diagnostic probes in identifying HTLVI- but not HTLVII-infected lymphoid cells in immunofluorescence assays. In addition to reacting with HTLVI p19, antibodies 2 and 4 also cross-reacted with a wide variety of HTLV-uninfected normal and neoplastic cells and tissues. In addition, HTLVI+ patient sera contained antibodies that competed for binding to the antigenic site on p19 recognized by antibody 4. Thus, anti-p19 monoclonal antibodies alpha HTLV-2 and 4 reacted with a 19,000-dalton viral-encoded protein of HTLVI and cross-reacted with normal host tissues, while anti-p19 antibody alpha HTLV-3 was specific for HTLVI p19 core protein.
Animals↗
Phenotypic and functional characterization of human malignant T cells.
Malignancies of thymus-derived (T) lymphocytes can be divided into two major groups: diseases of T cells expressing immature T cell markers (T-ALL, T cell lymphoblastic lymphoma) and diseases of malignant T cells expressing markers in a pattern similar to normal mature T cells (T cell CLL, ATL, various forms of CTCL, and T-PLL). Until specific pathways of normal cell maturation are known, the relationship of phenotypic expression of various T cell markers by malignant T cells to a particular stage of normal T cell differentiation must remain speculative. However, phenotypic characterization of malignant T cells is an important first step in the study of events that transpire in the development of T cell malignancies. Future parallel study into the mechanisms of normal and aberrant T cell maturation will undoubtedly lead to greater understanding of the pathogenesis of the T cell malignancies, and therefore pave the way for specific therapies for these difficult-to-treat syndromes.
Antibodies, Monoclonal↗
Human T cell antigen expression during the early stages of fetal thymic maturation.
Human thymus tissue was examined from 7 wk of gestation through birth for the expression of antigens reacting with a panel of anti-T cell monoclonal antibodies. Additionally, the reactivities of reagents against the transferrin receptor, against leukocytes, against low m. w. keratins, and against major histocompatibility complex antigens were studied on human fetal thymic tissue. Frozen tissue sections were evaluated by using indirect immunofluorescence assays. At 7 wk of gestation, no lymphoid cells were identified within the epithelial thymic rudiment; however, lymphoid cells reacting with both antibody 3A1, a pan T cell marker, and antibody T200, a pan leukocyte reagent, were identified in perithymic mesenchyme. After lymphoid colonization of the thymic rudiment at 10 wk of fetal gestation, fetal thymic tissue reacted with antibodies T1, T4, and T8. At 12 wk of gestation, antibodies T3, T6, A1G3 (anti-p80, a marker of mature thymocytes), and 35.1 (anti-E rosette receptor) all reacted with thymic tissue. Our findings indicate that T cell antigens were acquired sequentially on thymocytes at discrete stages during the first trimester of human fetal development. The 3A1 antigen was present on fetal lymphocytes before lymphoid cell colonization of thymic epithelium, suggesting that passage through the thymus was not required for the expression of the 3A1 antigen by T cell precursors. The appearance of mature T cell antigens, T3 and p80, on thymocytes by 12 wk of gestation implies that the T cell antigen repertoire may be established in the thymus during the first trimester. Thus, a critical period of T cell maturation appears to occur between 7 and 12 wk of human fetal gestation.
Antibodies, Monoclonal↗
Selective inhibition of natural killer activity by the monoclonal antibodies OKT10 and VEP10 at the single cell level.
The monoclonal antibodies, VEP10 and OKT10, which have been shown to recognize determinants on human natural killer (NK) cells, inhibit large granular lymphocyte (LGL) NK activity against K562, MOLT4, and CEM tumor target cells in the single cell conjugate agarose assay. Inhibition of NK activity by monoclonal antibodies was expressed independently of effector-target cell binding, as inhibitory activity could be demonstrated when the monoclonal antibodies VEP10 and OKT10 were added to preformed conjugates or to the LGLs and targets prior to the binding event. In addition, this inhibition was exerted on the effector cell and not the target cell since VEP10 and OKT10 did not react with determinants on K562 target cells. Furthermore, the 4F2 monoclonal antibody, which reacted with determinants on the LGL and all of the targets used, effected no inhibition of NK activity. Inhibition of killing by OKT10 and VEP10 was specific to endogenous NK activity since the same antibodies did not inhibit antibody-dependent cellular cytotoxicity (ADCC), mixed lymphocyte-generated NK, or cytotoxic T lymphocyte (CTL) activities.
Antibodies, Monoclonal↗
Frequent detection and isolation of cytopathic retroviruses (HTLV-III) from patients with AIDS and at risk for AIDS.
Peripheral blood lymphocytes from patients with the acquired immunodeficiency syndrome (AIDS) or with signs or symptoms that frequently precede AIDS (pre-AIDS) were grown in vitro with added T-cell growth factor and assayed for the expression and release of human T-lymphotropic retroviruses (HTLV). Retroviruses belonging to the HTLV family and collectively designated HTLV-III were isolated from a total of 48 subjects including 18 of 21 patients wih pre-AIDS, three of four clinically normal mothers of juveniles with AIDS, 26 of 72 adult and juvenile patients with AIDS, and from one of 22 normal male homosexual subjects. No HTLV-III was detected in or isolated from 115 normal heterosexual subjects. The number of HTLV-III isolates reported here underestimates the true prevalence of the virus since many specimens were received in unsatisfactory condition. Other data show that serum samples from a high proportion of AIDS patients contain antibodies to HTLV-III. That these new isolates are members of the HTLV family but differ from the previous isolates known as HTLV-I and HTLV-II is indicated by their morphological, biological, and immunological characteristics. These results and those reported elsewhere in this issue suggest that HTLV-III may be the primary cause of AIDS.
Acquired Immunodeficiency Syndrome↗
Monoclonal antibodies against human T cell leukemia-lymphoma virus (HTLV) p24 internal core protein. Use as diagnostic probes and cellular localization of HTLV.
Four monoclonal antibodies, human T cell leukemia-lymphoma virus (HTLV) 6, 7, 8, and 9, which react with the 24,000 dalton internal core protein of HTLVI, have been developed. These monoclonal antibodies reacted with only HTLV-infected cells and not with a broad spectrum of normal, neoplastic, mitogen-stimulated, or virus-infected cells and tissues. HTLV 6, 7, 8, and 9 identified at least two different antigenic determinants on HTLV p24 that were also recognized by antibodies present in HTLV+ patient sera. Monoclonal antibodies HTLV 6, 7, 8, and 9 reacted in indirect immunofluorescence assays with HTLV p24 localized at the cell surface of 5-d cultures of HTLV-infected T cells and, as well, reacted with T cells infected with HTLVII, a new type of HTLV isolated from a patient (MO) with a T cell variant of hairy cell leukemia. Thus, HTLV 6, 7, 8, and 9 should prove to be useful diagnostic reagents in the identification of HTLV- and HTLVII-infected T cells.
Animals↗
Phenotypic characterization and ontogeny of mesodermal-derived and endocrine epithelial components of the human thymic microenvironment.
Using murine monoclonal antibodies TE-4 and TE-7 raised against human thymic stroma, we identified two distinct and mutually exclusive thymic microenvironment components: the thymic endocrine epithelium (TE-4+) and mesodermal-derived fibrous stroma (TE-7+). TE-4-reactive epithelium did not react with antibody TE-7, contained thymosin alpha 1 and keratin, and expressed other known markers of thymic endocrine epithelium (A2B5 and p19). Moreover, TE-4+ thymic epithelial cells strongly expressed class I (HLA-A, -B and -C) and class II (Ia-like) major histocompatibility complex (MHC) antigens. In contrast, TE-7+ thymic fibrous stroma did not react with antibody TE-4, did not contain thymosin alpha 1 nor keratin, and did not express the thymic endocrine epithelium markers A2B5 and p19. TE-7+ thymic stromal cells weakly expressed class I and did not express class II MHC antigens. Both TE-4+ and TE-7+ thymic microenvironment compartments were identifiable in thymus from 7 wk gestation through adult life. At 7 wk fetal gestation, TE-7+ stroma surrounded a cylindrical TE-4+, A2B5+ thymic epithelial rudiment. Between 10 and 15 wk fetal gestation, TE-7+ thymic stroma surrounded early thymic lobules. By 15 wk fetal gestation, antibody TE-4 defined subcapsular cortical and medullary zones of endocrine thymic epithelium, while antibody TE-7 bound to interlobular fibrous septae, vessels, and thymic fibrous capsule. While otherwise specific for endocrine thymic epithelium, antibody TE-4 reacted with the basal layer of squamous epithelium in skin, tonsil, conjunctiva, and upper esophagus.
Adolescent↗
Rheumatoid arthritis and sterile corneal ulceration. Analysis of tissue immune effector cells and ocular epithelial antigens using monoclonal antibodies.
Tissue immune effector cells and epithelial surface antigens present in eye tissue of rheumatoid arthritis (RA) patients with sterile corneal ulceration were studied using a large panel of monoclonal antibodies. During periods of active corneal ulceration, conjunctivae and corneas of all RA patients studied contained numerous immune-associated (Ia) antigen-positive tissue macrophages. In 4 of 6 patients, conjunctival or corneal T cell infiltrations were present. In 2 patients, a T cell vasculitis was seen in conjunctival tissue. Conjunctival epithelial cells of all 6 RA patients expressed Ia antigens during active corneal ulceration. These data provide evidence for immune-mediated mechanisms in the pathophysiology of corneal ulceration in RA. Moreover, the expression of Ia antigens by conjunctival epithelial cells may be a useful indicator of disease activity in RA patients with sterile corneal ulceration.
Adult↗
Leukemia-associated arthritis: identification of leukemic cells in synovial fluid using monoclonal and polyclonal antibodies.
Explore the source record for details and available documents.
Adult↗
Thymoma: lymphoid and epithelial components mirror the phenotype of normal thymus.
Six thymomas were studied with monoclonal and polyclonal antisera and an immunohistochemical technique to characterize the lymphocytic and epithelial components of the tumor. The T lymphocytes had characteristics of thymocytes, and cortico medullary differentiation was demonstrated within all tumors, regardless of histologic appearance. Cortical thymocytes were positive with anti-terminal deoxynucleotidyl transferase, OKT6, and OKT10, all of which failed to stain medullary thymocytes. Conversely, A1G3 stained medullary thymocytes exclusively. Epithelial cells reacted with A2B5, an antibody that identifies cells of neuroendocrine origin. Epithelial cell processes were also positive with anti-p19, a monoclonal antibody directed against the internal protein of HTLV, which also reacts with normal thymic epithelium. No correlation was found in the distribution of epithelial cells with evidence of cortical and medullary thymocyte differentiation. However, the components of the tumor mirrored the normal cellular and structural components of the thymus.
Antibodies, Monoclonal↗
The human thymic microenvironment.
Several major points should be emphasized that provide directions for future research. First, using monoclonal reagents we have been able to phenotypically identify four major regions of the human thymus microenvironment: the thymic capsule, interlobular septae and stroma (TE-7+), the subcapsular cortex (TE-4+, Thy-1+, A2B5+, anti-p19+, BB TECS+, TE-3+), the cortex (TE-3+), and the medulla (TE-4+, A2B5+, anti-p19+, BB TECS+). TE-4+ and TE-3+ thymic epithelium constitute HLA+, Ia+ subsets of thymic epithelium that are candidates for cell types of the human thymic microenvironment that might participate in conferring MHC restriction to maturing T lymphocytes. TE-7+ stroma most likely represents the mesodermal-derived thymic component that early in development induces thymic epithelial differentiation. Second, whereas TE-4, anti-p19, and BB TECS antibodies may be thymic epithelial lineage markers, they all react with the basal layer of squamous epithelium of various organs. In particular, in the tonsil, A2B5+, TE-4+ epithelium splays out in the base of tonsillar crypts and morphologically appears similar to thymic medullary epithelial cells. Therefore, these markers of endocrine thymic epithelium may also identify extrathymic areas of T cell differentiation. Third, the concept that thymic epithelium is constantly differentiating in the developed thymus is suggested by the coexpression of TE-4, TE-8, TE-16, and TE-15 antigen by layers of squamous epithelial keratinocytes and by thymic epithelium. That there is a TE-4/TE-8/TE-15 keratinocyte maturation pathway in skin gives credence to the notion that a similar pathway exists from TE-4+, TE-8-, TE-15- endocrine medullary epithelial cells to TE-4-, TE-8+, TE-15+ Hassall's bodies. Fourth, from the literature and the work presented in this review, three phases of thymic microenvironment development can be defined. The first phase is during early fetal development (4 to 8 weeks in humans) when mesodermal-derived fibrous tissue induces endodermal and ectodermal-derived thymic epithelium to proliferate and mature. TE-7+ mesenchymal stroma invaginates TE-4+ thymic epithelium and effects thymic lobulation. The second phase occurs between 9 and 15 weeks fetal development when the thymic primordia is colonized by blood-borne thymocyte precursors. Presumably during this stage, thymic epithelium promotes bone marrow cell colonization of thymus by producing chemoattractant molecules.(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗
Early corneal findings in Cogan's syndrome.
We evaluated the ocular manifestations of Cogan's syndrome in 13 consecutive patients. The most frequent and earliest ocular finding was bilateral peripheral subepithelial keratitis consisting of faint, nummular lesions. The subepithelial keratitis was responsive to topical administration of corticosteroids. Peripheral subepithelial keratitis was seen in four patients and strongly suspected on review of history in three additional patients. Deep stromal keratitis was seen in two patients, while only one patient developed classic findings of Cogan's syndrome, ie. interstitial keratitis with vascularization. Additionally, five patients presented with noncorneal ocular inflammatory disease and deafness (atypical Cogan's syndrome). Early subepithelial keratitis in Cogan's syndrome may be mistakenly diagnosed as trival ocular inflammatory disease, and suppressed by topical corticosteroids, resulting in delayed diagnosis of Cogan's syndrome in the absence of classic corneal findings. Early diagnosis of Cogan's syndrome is important inasmuch as prompt treatment of cochlear symptoms with systemic corticosteroids may prevent or ameliorate deafness.
Adolescent↗
Conversion of a stem cell leukemia from a T-lymphoid to a myeloid phenotype induced by the adenosine deaminase inhibitor 2'-deoxycoformycin.
Selective failure of lymphoid development occurs in genetic deficiency of adenosine deaminase (ADA). We examined the in vivo effects of a potent inhibitor of ADA, 2'-deoxycoformycin, which was used to treat a patient with refractory acute leukemia. Unexpectedly, within 7 days of starting treatment, the leukemic phenotype underwent complete conversion from T lymphoblastic to promyelocytic, with kinetics that suggested a precursor-product relationship between the two cell populations. Pretreatment T lymphoblasts and posttreatment promyelocytes had the same abnormal karyotype. Upon culture in vitro, the former transformed spontaneously over several weeks into mature myeloid cells. We conclude that the leukemia arose from a multipotent stem cell capable of both lymphoid and myeloid differentiation. Effects of ADA inhibition on leukemia cells during treatment included expansion of the deoxyadenosine nucleotide pool and accumulation of S-adenosylhomocysteine, a potent inhibitor of S-adenosylmethionine-dependent methylation. The influence of these changes on the leukemic phenotype is discussed in terms of (i) selective cytotoxicity to T lymphoblasts, which accumulated deoxyadenosine nucleotides more efficiently than did the patient's promyelocytes during in vitro incubation with deoxycoformycin plus deoxyadenosine, and (ii) induction of an altered program of differentiation.
Acute Disease↗