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Biomedical subjects

J Forman

Publications and source records attributed to J Forman.

At least 91 records · Page 5Linked to original sources
PubMed1984

Cytotoxic T lymphocytes recognize determinants on the BALB/c-H-2Ld molecule controlled by alpha 1 and alpha 2 but not alpha 3 external domains.

We have shown that cytotoxic T lymphocytes (CTL) raised in H-2d mice use H-2Ld but not H-2Dd or H-2Kd antigens as restricting elements in lymphocytic choriomeningitis virus (LCMV) and vesicular stomatis virus (VSV) infections. To localize the regions of H-2Ld protein recognized by CTL, we constructed a recombinant H-2Ld/Dd gene encoding a hybrid antigen with alpha 1 and alpha 2 external domains of H-2Ld and alpha 3, transmembrane and cytoplasmic domains of H-2Dd. The recombinant gene was transfected into mouse cells and the hybrid molecules were characterized serologically, biochemically and functionally. In all assays, H-2Ld/Dd molecules were recognized by LCMV-and VSV-specific H-2Ld-restricted CTL in a manner similar to that of wild-type H-2Ld antigens. Analogous results were obtained with alloreactive CTL. Hybrid antigens containing the alpha 3 domain of H-2Ld fused to alpha 1 and alpha 2 domains of a Qa-2,3 region-encoded antigen were not used as restricting elements by LCMV-specific CTL. These results suggest that H-2Ld-restricted CTL directed against LCMV and VSV recognize determinants controlled by the alpha 1 and/or alpha 2 domains of the H-2Ld molecule.

Animals↗
PubMed1984

T cells, the MHC, and function.

The model presented relates the class of MHC molecule recognized with the activity of T lymphocytes. This occurs by postulating that the function of MHC molecules is to present determinants to differentiation directing (D) receptors on T lymphocytes. These D receptors are distributed nonclonally and interact with nonpolymorphic determinants on MHC molecules which are normally inaccessible. The result of this interaction is to allow for the expression of a functional phenotype for the T cell providing that helper signals are present. In the case of alloreactive CTL that recognize class II or Th that recognize class I molecules we postulate that these T cells require the presence of class I or class II molecules, respectively, on the target cell. Recognition of antigen in the absence of helper signals leads to tolerance of both Th.P and CTL.P. Since helper signals are required for the activation of CTL.P, a lack of specific Th, determined by class II alleles, will prevent development of a proportion of the CTL repertoire.

Animals↗
PubMed1984

H-40, an antigen controlled by an Igh-linked gene and recognized by cytotoxic T lymphocytes. II. Recognition of H-40 as a tumor antigen in leukemic animals.

C.B-20 (Ighb) but not (C.B-20 X BALB/c)F1 mice reject BCL1, a sIg+ tumor that spontaneously arose in an Igh congenic BALB/c (Igha) mouse. C.B-20 immune T cells from mice immunized with either BCL1 or BALB/c splenocytes adoptively transfer tumor protection to sublethally irradiated C.B-20 but not BALB/c or (BALB/c X C.B-20)F1 mice. These data suggest that BALB/c and BCL1 share an antigen, which if present in the host prevents the immune cells from eradicating the tumor. The antigen is controlled by H-40, a gene that maps to the C end of the Igh complex, telomeric to Tsu and in the region of Pre-1. The ability of H-40 to act as a tumor antigen for other BALB/c tumors inoculated into C.B-20 hosts was investigated. H-40 did not elicit rejection of P1798 (T lymphoma), Meth A (fibrosarcoma), or MOPC-315 (alpha, lambda myeloma) tumor cells. C.B-20 mice that previously rejected BCL1, however, showed partial resistance to a low challenge dose of the MOPC-104E (mu, lambda myeloma) tumor. These data suggest that H-40 has a differential degree of expression on BALB/c tumor cells. The ability of the adoptively transferred cells to confer protection against BCL1 is abrogated by pretreatment of the cells with anti-Lyt-1 or anti-Lyt-2 antibodies. However, an admixture of anti-Lyt-1- and anti-Lyt-2-treated cells provided protection. These data, together with the results detected by cytotoxic T lymphocyte (CTL) activity in vitro, indicate that H-40 can serve as a target antigen for tumor rejection by CTL in allogeneic hosts. The implications of the results for allogeneic bone marrow transplantation into leukemic individuals who benefit from a graft vs leukemia effect are discussed.

Animals↗
PubMed1983

Use of DNA-mediated gene transfer to analyze the role of H-2Ld in controlling the specificity of anti-vesicular stomatitis virus cytotoxic T cells.

Mouse thymidine kinase (tk-) C3H L (H-2k) cells transformed by the technique of DNA-mediated gene transfer with the herpes simplex virus tk gene together with the BALB/c H-2Ld gene express H-2Ld molecules indistinguishable from their counterparts on spleen cells. An established cloned cell line (8-5) was used to assess the function of the H-2Ld antigen in determining the specificity of alloreactive as well as anti-vesicular stomatitis virus (VSV) cytotoxic T cells (CTL). Both anti-H-2d and anti-H-2Ld CTL displayed a cytotoxic effect against 8-5 cells but not a control cell line transformed with the tk gene only (tk+ cells). Further evidence that 8-5 cells express H-2Ld was provided by the finding that monoclonal anti-H-2Ld but not H-2Dd antibodies blocked target cell lysis by the effector cells. Both BALB/c (H-2d) and DBA/2 (H-2d) animals generated anti-VSV CTL that lysed infected 8-5 but not tk+ cells. To further establish that H-2Ld controlled the specificity of the effector cells, a monoclonal antibody directed against H-2Ld was shown to inhibit lysis of infected 8-5 target cells. To determine whether other H-2d-encoded gene products could serve as restricting antigens for anti-VSV CTL in BALB/c animals, unlabeled VSV infected 8-5 cells were tested for their ability to block lysis of 51chromium-labeled P815 (H-2d)-infected target cells. The 8-5-VSV inhibitor cells inhibited lysis to a slightly lesser extent than unlabeled P815-VSV cells, indicating that H-2Ld plays a major if not exclusive role in restricting anti-VSV CTL in H-2d animals.

Animals↗
PubMed1983

Expression and function of transplantation antigens with altered or deleted cytoplasmic domains.

Two mutants of the class I gene encoding the H-2Ld transplantation antigen have been constructed. In one mutant the cytoplasmic domain of the class I molecule has been altered by deletion of 24 of the 31 C-terminal residues, and in the second the C-terminal 25 residues of the cytoplasmic domain have been replaced with a unique sequence of 19 amino acids. These mutant class I genes have been transferred into mouse L cells by DNA-mediated gene transfer. Both mutant genes are expressed at normal levels on the cell surface, and they have charge properties and sizes consistent with the introduced alterations. These mutant Ld molecules can serve as target antigens for allogeneic cytotoxic T cells and as restricting elements for virus-specific cytotoxic T cells. These results show that the 24 residues replaced or deleted from the carboxy terminus of the class I molecule are not required for its transport to or integration in the plasma membrane, nor for its function as a target antigen or a restricting element during T-cell-mediated cytotoxicity.

Amino Acid Sequence↗
PubMed1983

Non-invasive quantification of aortic regurgitation by Doppler echocardiography.

This study was undertaken to assess the contribution of Doppler echocardiography to the quantification of aortic valve regurgitation. Ultrasound examination was performed by recording aortic arch blood flow from the suprasternal notch. A non-invasive index of valve regurgitation was obtained by calculating the ratio between the maximal amplitude of forward flow during systole and the amplitude of retrograde flow during diastole measured at the onset of the R wave of the electrocardiogram. This index was compared with semiquantitative data derived from supravalvular aortography in 93 patients. In pure aortic regurgitation (67 patients) the results showed a high correlation coefficient between Doppler and angiographic estimates. In cases of associated aortic valve stenosis there were problems in the accurate estimation of systolic blood flow which led to global overestimation in general of the degree of regurgitation and considerable lack of precision in individual patients. But in general Doppler echocardiography appeared to be a successful technique to quantify pure aortic regurgitation.

Adolescent↗
PubMed1983

Quantitative assessment of tricuspid regurgitation using pulsed Doppler echocardiography.

Tricuspid valve regurgitation was assessed quantitatively by measuring blood flow velocity in the vena cava using a pulsed Doppler velocimeter. A non-invasive index of regurgitation was obtained by calculating the ratio between the maximum amplitudes of the systolic and diastolic components of the velocity curves. The index was compared with the angiographic grading of regurgitation in 70 patients after right heart catheterisation; the results were closely correlated. Using the Doppler index the differences between the groups defined according to their angiographic grade were significant. Thus measurement of blood flow velocity in the vena cava appears to quantify accurately the severity of tricuspid regurgitation.

Adolescent↗
PubMed1983

Allogeneic and associative recognition determinants of H-2 molecules.

Data presented here describe recent attempts to understand the structural basis for H-2 function. Inbred strains differing only by point mutation in different regions of H-2Kb have proven valuable in the analysis of H-2 domain function. Evidence for the interaction between the N and C1 domains in forming allorecognition determinants and antigen interaction sites is shown. The functional role of C2 is not yet known, since no mutations have been found there, but DNA-mediated gene transfer and exon shuffling techniques should prove invaluable in addressing this issue. Ir gene-type functions of class I molecules were demonstrated. The inability of low responder mutant strains to cross-react with H-2Kb-restricted CTL suggests that these phenomena reflect the failure of virus antigen to interact with low responder H-2Kbm molecules. Thus, the mutant strains provide a valuable system for investigating class I Ir genes.

Animals↗
PubMed1983

[Conduction disorders and aneurysms of the sinus of Valsalva].

A series of 15 sinus of Valsalva aneurysms (SVA) admitted between 1961 and 1981 was reviewed to analyse associated conduction defects. It comprised 11 men and 4 women; the mean age was 31 years (range 16 to 53). The diagnosis of SVA was made at the time of rupture (4 cases), during investigation of associated cardiac disease (8 cases), at surgery (1 case) and during advanced conduction disorders (2 cases). All patients underwent catheterisation and angiography. Endocavitary electrophysiological studies were performed in 3 patients. Eight out of 15 patients had conduction defects which comprised: incomplete right bundle branch block (2 cases), atrioventricular block (AVB) (6 cases). Endocavitary investigation of 3 of the 6 AVB showed conduction defects at several levels: sino atrial, suprahisien, intrahisian and infrahisian blocks (1 case); transient complete AVB with 1 degree and 2 degree intrahisian block (1 case); complete AVB, six years after correction of SVA, due to infrahisian block (1 case). Thirteen of the 15 patients underwent surgery; none of the 9 cases of SVA without conduction defects before surgery developed conduction defects. Four of the 6 cases of AVB required permanent pacing; there was 1 postoperative death. One patient was not operated. These conduction defects were caused by the close relationship of the SVA to the intracardiac conduction pathways. The right anterior was the most commonly affected sinus. The investigation of AV conduction should be systematic in cases of SVA, and, conversely, the finding of AVB in young patients should alert the physician to the possibility of a SVA.

Adolescent↗
PubMed1983

[Dissection of the ascending aorta after aortic valve replacement].

Three patients who underwent aortic valve replacement had dissection of the ascending aorta 7 months, 2 years and 15 years after surgery. This is a rare complication of aortic valve replacement (11 reported cases). Its incidence estimated from the literature would appear to be less than 1% of all aortic valve replacements. It occurs in both cases of stenosis and regurgitation (4 aortic regurgitations, 2 aortic stenosis, 5 mixed aortic valve disease) and is seen in ball and cage (7 cases), tilting disc (3 cases) and bioprosthesis (1 case). Six of these patients had hypertension. The role of the initial surgery for valve replacement in secondary aortic dissection is discussed. Aortic clamping and cannulation can cause immediate dissection but may also damage the aortic wall, leading to the risk of secondary dissection. An aneurysm of the ascending aorta was observed in 5 Cases at surgery; in 3 cases, the aorta was dilated without true aneurysm; in 3 other cases the aorta was considered to be macroscopically normal. The integrity aorta is sometimes difficult to confirm and a macroscopically normal of the aorta may have fragile aortic walls, especially in cases of aortic regurgitation due to valvular dysplasia and forms frustres of Marfan's syndrome, and are associated with a risk of secondary dissection. The appearances of the aorta at aortic valve replacement influence the choice of treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1982

H-2L-restricted recognition of viral antigens In the H-2d haplotype, anti-vesicular stomatitis virus cytotoxic T cells are restricted solely by H-2L.

H-2d-encoded gene products were analyzed as restriction antigens for anti-vesicular stomatitis virus (VSV) cytotoxic T lymphocytes (CTL). Cold target competition experiments revealed that VSV recognition was H-2D region-restricted; H-2K-end-restricted recognition of VSV could not be demonstrated. That VSV is not recognized in the context of K-region-encoded gene products is also supported by the observation that H-2dm1 and H-2dm2 mice, strains that contain H-2Kd but have an alteration in H-2L and/or H-2D/L, are nonresponders in the CTL assay. Two different lines of evidence eliminated H-2Dd, H-2Md, and H-2Rd as the restriction antigens: (a) H-2dm2-VSV inhibitors that express H-2Dd and H-2Md did not block the lysis of P815-VSV targets by Balb/c anti-VSV killer cells, and (b) a hybridoma specific for H-2Dd failed to inhibit killer cell activity in this same effector/target combination. However, two monoclonal antibodies specific for H-2Ld but not H-2Rd completely blocked anti-VSV cytotoxic activity. Taken together, in the H-2d haplotype, anti-VSV CTL recognize VSV solely in the context of the H-2Ld molecule. This is the first demonstration of the exclusive use by a mouse stain of the H-2L molecule only for H-2-restricted recognition, and thus supports the notion that H-2L plays a major role in restricting antigen specific recognition. Finally, the fact that an anti-H-2Ld monoclone completely blocked an H-2dm2 anti-BALB/c CTL response indicates that H-2R, a molecule absent in H-2dm2 anti-BALB/c CTL response indicates that H-2R, a molecule absent in H-2dm2 but not BALB/c, does not sensitize H-2 alloreactive CTL.

Animals↗
PubMed1982

The Qa2 subregion controls the expression of two antigens recognized by H-2-unrestricted cytotoxic T cells.

B6.KI mice were immunized with spleen cells from B6.K2, a Qa2-subregion congenic strain. Cytotoxic T cells were generated that recognize two target antigens controlled by this region. One of the target antigens is Qa-2. This was demonstrated by the findings that pretreatment of target cells with monoclonal anti-Qa-2 antibody blocked lysis of target cells, and Qa-2 target antigens and serological determinants had a concordant distribution on a panel of B10.W (wild) mice. The gene controlling the Qa-2 target antigen is not polymorphic because B6.K2 and three strains of Qa-2(+) B10.W mice express the same antigens, as determined by a CTL cold target competition assay. Anti-Qa-2 CTL were H-2 unrestricted because effector cells lysed Qa-2(+) targets irrespective of their H-2 haplotype, including five B 10.W strains, and lysis was not inhibited by pretreating target cells with anti-H-2 sera. The Qa2 subregion does not act as a restricting locus for anti-minor-H antigen CTL. A second target antigen was detected that was associated with the expression of the Qa-5 determinant. However, CTL activity could not be blocked by pretreating target cells with monoclonal anti-Qa-5. Therefore, the CTL target antigen may be expressed on a Qa-5(-) molecule. Although the Qa-5 associated CTL specificity is only detected on H-2D(b) strains, it is unlikely that CTL recognition is H-2 restricted because anti-H-2(b) sera has no effect in blocking this reactivity. Qa-2 and H-2 class I antigens share a similar structure and serve as target antigens for unrestricted CTL. However, unlike class I H-2 genes, Qa-2 neither restricts antigen-specific CTL nor is polymorphie. Therefore, it is likely that Qa-2 and H-2 are derived from a common ancestral gene and have evolved to serve different functions.

Animals↗
PubMed1982

Helper activity is required for the in vivo generation of cytotoxic T lymphocytes.

B6.T1a(a) (Qa-1(a)) mice that are primed in vivo and restimulated in vitro with Qa-1 congenic spleen cells from B6 (Qa-1(b)) animals are unable to generate anti-Qa-1(b) cytotoxic T lymphocytes (CTL). This nonresponsive pattern was observed regardless of the route of immunization or the time of testing in vitro. Although B6.T1a(a) mice are nonresponders to Qa-1(b) when presented on B6 cells, these mice can generate anti-Qa-1(b) CTL when primed in vivo with Qa-1 and H-Y alloantigens (females primed with B6 male cells) or Qa-1 and minor-H- alloantigens (primed with sex-matched A.BY cells). Therefore, the inability to generate anti-Qa-1(b) CTL is due to a lack of helper or accessory antigens on B6 immunizing cells obligatory during in vivo priming, rather than an absence of anti-Qa-1(b) CTL precursors (CTL-P). Demonstration that the additional determinants required during in vivo priming actually function as carrier or helper determinants was shown by the requirement for linked recognition of Qa-1 and the helper determinants (H-Y) in vivo, and the fact that H-Y was not present on susceptible target ceils. Animals primed in vivo with H-Y only could not generate anti-Qa-1 CTL activity when challenged in vitro with both Qa-1 and H-Y, indicating that recognition of the helper determinant causes in vivo priming of CTL-P rather than generating helper activity that might activate unprimed CTL-P in vitro. Whereas unprimed peripheral CTL-P require the presence of both Qa-1 (CTL) and H-Y (helper) determinants for successful in vivo priming, helper determinants were not required in vitro because primed CTL-P from B6.T1a(a) mice could be driven to CTL in vitro using sex-matched B6 stimulator cells. The generation of anti-Qa-1(b) CTL is under immune response (Ir) gene control because F(1) mice, obtained by crossing responder A/J with nonresponder B6.T1a(a) animals, generated CTL to the Qa-1(b) alloantigen when presented on B6 spleen cells. Progeny testing of backcross mice further demonstrated that the Ir gene(s) is linked to the H-2 complex. These data indicate that an H-2-linked Ir gene controls the recognition of helper determinants required for CTL priming in vivo. These helper determinants can be distinguished from CTL determinants and both must be recognized together for successful priming of CTL-P.

Animals↗
PubMed1982

[Non-invasive study of aortic insufficiency by Doppler echocardiography].

The possibilities of diagnosis and quantification of aortic regurgitation by pulsed Doppler analysis of blood flow in the aortic arch were examined in 60 patients aged between 9 and 67 years old. Aortic flow curves were recorded from the suprasternal area with the sample volume positioned at the junction of the horizontal part of the aortic arch and the descending aorta. Normal flow curves are characterised by an anterograde systolic wave with a brief proto-diastolic reflux. In aortic regurgitation holodiastolic reflux is observed. An index of regurgitation may be calculated from the ratio of the amplitude of end diastolic reflux measured on the R wave of th ECG and the maximal amplitude of anterograde systolic flow. This ratio eliminates the factor related to the incident angle between the ultrasound beam and the direction of blood flow. The values of this ratio were compared to the semi quantitative assessment of aortic regurgitation from ascending aortic angiography. The only false negatives were observed in patients with negligible regurgitation (grade I). One false positive result was obtained in a patient in whom it was difficult to obtain the recording and in whom the value of the ratio was very low (0,02). Global specificity was 91 p. 100 and sensitivity was 82 p. 100. The sensitivity for average or severe regurgitation was 100 p. 100. The correlation coefficient between the Doppler index or regurgitation and the semi quantitative angiographic estimation was 0,69. In patients with pure aortic regurgitation the correlation reached 0,85 (p less than 0,001). The differences between the different groups then became highly significant.

Adolescent↗