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Biomedical subjects

E Martz

Publications and source records attributed to E Martz.

At least 19 recordsLinked to original sources
PubMed2003

Death anxiety as a predictor of future time orientation among individuals with spinal cord injuries.

PURPOSE: The purpose of this study was to examine the relationship between death anxiety and future time orientation among individuals who sustained spinal cord injuries (SCI). METHODS: Participants were 317 individuals with SCI, of whom 57.4% were US veterans. Data were obtained by means of mailed questionnaires and included responses to the Death Anxiety Scale (DAS), the Future Time Orientation (FTOS) measure, as well as information on participants' personal and disability-related characteristics. RESULTS: A hierarchical multiple regression analysis was conducted to examine the influence of a set of demographic variables, followed by a set of disability-related variables, and finally two factorially-derived measures of death anxiety (denial of death and distressed awareness of death) on future time orientation. Two disability-related variables (pain level and existence of pressure ulcers) and one of the two death anxiety measures (distressed awareness of death) significantly predicted future time orientation. A post-hoc analysis, adding depression as a predictor, was also significant, indicating that an increased level of depression uniquely contributed to a truncated future time orientation. CONCLUSIONS: Distressed anxiety and depression may be important factors affecting goals and plans of people with SCI. Future research should attempt to clarify the intricate relationships among negative affectivity, future time orientation, and psychosocial adaptation to SCI.

Adolescent↗
PubMed1992

How do CTL control virus infections? Evidence for prelytic halt of herpes simplex.

Cytotoxic T lymphocytes (CTL) induce in target cells a rapid, prelytic fragmentation of target cell DNA, accompanied by apoptosis. In contrast, complement and (with a few exceptions) chemical and physical means of inducing cytolysis induce necrosis, without DNA fragmentation. The function of the unusual DNA fragmentation induced by CTL remains to be elucidated. The major recognized function of CTL is in halting virus infections. Earlier, we proposed that CTL might halt virus infections prelytically, by fragmenting viral and cellular nucleic acids, and that in this case, cytolysis per se might be a less important function of CTL. We report here experiments designed to detect prelytic halt of virus replication. We employed in vivo-like conditions: fibroblast targets (difficult to lyse) were infected with herpes simplex virus (HSV), then incubated at low E/T cell ratios overnight. At the highest E/T ratios which produced less than 10% CTL-induced lysis, plaque-forming unit yield was reduced by about 50%. At higher E/T ratios which lysed 1/6 to 1/3 of the infected target cells, 3/4 to 9/10 of the virus production was prevented. The discrepancy between the level of lysis and the reduction in virus yield is evidence for significant CTL-induced prelytic halt of HSV replication. At present, it is unclear whether the antiviral effect observed involves an activity of CTL distinct from their lytic ability, such as their DNA fragmenting ability.

Animals↗
PubMed1991

Cytoskeletal function in CD8- and T cell receptor-mediated interaction of cytotoxic T lymphocytes with class I protein.

Cloned allospecific cytolytic T lymphocytes (CTL) adhere to purified class I alloantigen immobilized on plastic and degranulate in response to it. Binding and degranulation are inhibited by drugs that impair cytoskeletal function. Cytochalasins D and E, which interfere with microfilament function, and colchicine, which disrupts microtubules, were used and gave qualitatively similar results. Concentrations of these drugs that inhibited degranulation in response to alloantigen did not inhibit response to immobilized anti-T cell receptor (TCR) antibody. Neither did they inhibit response when alloantigen was co-immobilized with an antibody against class I on the CTL to promote adhesion between the CTL and antigen-bearing surface. Thus, neither transmembrane signal generation via the TCR nor degranulation per se were prevented. Instead, the drugs act to prevent the initial adhesion to alloantigen. CTL binding to alloantigen depends in part on CD8-class I interaction, and adhesion via CD8 is "activated" by crosslinking the TCR with soluble anti-TCR antibody. This adhesion, too, is shown to be cytoskeleton dependent.

Animals↗
PubMed1989

CTL: virus control cells first and cytolytic cells second? DNA fragmentation, apoptosis and the prelytic halt hypothesis.

It is usually presumed that cytotoxic T lymphocytes (CTL) stop viral replication by lysing infected cells before a full virus yield has been assembled. Unlike complement-mediated lysis, however, CTL induce apoptosis, including fragmentation of target cell DNA. Why should CTL do this? Here, Eric Martz and Donna Howell suggest that since the major function of CTL appears to be control of viruses, CTL may be able to halt viral replication without inducing rapid lysis. It may be more useful to think of CTL as virus control cells rather than as cytolytic cells.

DNA↗
PubMed1988

Low calcium concentrations support killing by some but not all cytolytic T lymphocytes, and reveal inhibition of a postconjugation step by calcium antagonists.

Previous findings support the prediction that drugs which antagonize the action of calcium should inhibit cytolytic T lymphocyte (CTL)-mediated killing without inhibiting the formation of Ag-specific CTL-target cell conjugates. This would contrast with other CTL-inhibiting drugs, nearly all of which inhibit conjugate formation. Testing this prediction, we found that two calcium channel blockers (verapamil and ruthenium red) inhibit killing only when the extracellular calcium concentration is low (100 microM), and, as predicted, do not inhibit conjugate formation. Surprisingly, the esterase inhibitor N alpha-p-tosyl-L-lysine choloromethylketone also inhibited killing without inhibiting conjugate formation. Unexpectedly, we found that the amount of calcium required by CTL varies by four-fold or more. CTL produced in vivo, or by a single Ag stimulation cycle in vitro, require more than 130 microM calcium for optimal killing, whereas 30 microM suffices for CTL primed in vivo plus boosted in vitro. The rate of admission of calcium into the cytoplasm by physiologic channels did not appear to be the limiting factor for the former type of CTL. Recent findings indicate that allospecific CTL produced in vivo may lack cytoplasmic granules, and may kill by an unidentified mechanism distinct from the exocytosis of granules prominent in CTL lines or clones maintained in vitro. The differences in calcium requirements reported here may reflect differences in mechanisms of killing.

Calcium↗
PubMed1988

Nuclear disintegration induced by cytotoxic T lymphocytes. Evidence against damage to the nuclear envelope of the target cell.

CTL and NK cells induce nuclear disintegration in their target cells. This phenomenon, which is seen as extensive fragmentation and solubilization of target cell DNA, is not seen with most other means of inducing cytolysis, including antibody- and complement-mediated cytolysis. We have previously shown that the degree of DNA solubilization is dependent upon the nature of the target cell. We here investigate the possibility that CTL induce, in all targets, damage to the nuclear envelope, which in turn leads to nuclear disintegration in only some of them. We reasoned that damage to the nuclear envelope would render nuclear DNA more accessible to exogenous DNase. Therefore, we determined the susceptibility of target DNA to exogenous DNase I after cytolysis by various means. We found no difference in DNA susceptibility for cells lysed by CTL vs methods (such as complement-mediated lysis or nonionic detergent) incapable of inducing nuclear disintegration. As a positive control, freezing and thawing dramatically enhanced susceptibility of the DNA. In conclusion, we found no evidence that the nuclear envelope is damaged by CTL in target cell types (or in the subpopulation of nuclei) that do not undergo nuclear disintegration.

Cell Line, Transformed↗
PubMed1987

The degree of CTL-induced DNA solubilization is not determined by the human vs mouse origin of the target cell.

CTL-mediated lysis is unique among lytic mechanisms in inducing rapid, prelytic nuclear disintegration. Target cell DNA can be solubilized within minutes as a result of degradation, which can proceed to the nucleosomal level, presumably mediated by endonucleases that are either endogenous or injected by the CTL. Nuclear disintegration has been reported for mouse lymphoid target cells by several groups. However, previous studies in which human target cells were studied saw little or no DNA solubilization. We here report rapid, extensive CTL-induced solubilization of DNA in human lymphoid target cells; on the other hand, we found that three mouse cell lines exhibit little or no nuclear disintegration. We conclude that the degree of nuclear disintegration depends on the nature of the target cell, but is not determined by the species of origin of the target cell.

Animals↗
PubMed1987

LFA-1 and other accessory molecules functioning in adhesions of T and B lymphocytes.

Adhesions of lymphocytes, among themselves or with other cell types, are necessary for most steps in immune responses including both induction and effector phases. Among adhesions of T cells involving specific immunological recognition, CTL-target adhesions have been the most studied. Although CTL-mediated killing is highly specific (specific/nonspecific lytic activity 50-fold), CTL-target adhesion (conjugation) is less so. In the mouse, specificity of conjugation has typically been four to eightfold. Two recent studies with cloned human CTL found much less specificity of conjugation, from one-fold (no specificity) to 1.5-fold. Thus, with cloned human CTL, adhesion may occur promiscuously with any potential target; recognition following adhesion is necessary for lethal hit delivery. The fact that antibodies to the antigen receptor (Ti or CD3) inhibit killing without inhibiting CTL-target conjugation supports this view. The ability of lymphocytes to form nonspecific adhesions, plus the dependence of even the specific mouse adhesions on temperature, metabolic energy, magnesium, and an intact cytoskeleton suggest that the bulk of the strength of T lymphocyte adhesions are not simply the sum of the bonds between antigen receptors (Ti) and antigen. Lymphocytes evidently possess separate "adhesion strengthening" mechanisms. The similarities in the properties of CTL-target adhesions and antigen-independent homotypic B lymphocyte adhesions (Table 2) suggest that at least some of these mechanisms are widely used among cells of hematopoietic origin. MoAbs to most lymphocyte surface molecules, when bound to the living lymphocyte membrane, have no evident functional effects on lymphocyte function. However, a minority can either activate or inhibit lymphocyte functions. Such antibodies identify "leukocyte (or lymphocyte) function-associated antigens," or LFAs (not all of which happen to have "LFA" in their names, Table 1). Most of the inhibitory antibodies inhibit lymphocyte adhesions, and this appears to account for their inhibitory effects on functions such as killing or proliferation. The fact that the binding of antibodies to a particular membrane glycoprotein inhibits adhesion does not guarantee that the glycoprotein in question is a direct participant in adhesion (one of the "glue" molecules). However, there is scanty evidence in support of indirect "negative signals" that may be induced by such antibodies, and direct participation of most LFAs in adhesion seems likely.(ABSTRACT TRUNCATED AT 400 WORDS)

Antigens, Differentiation, T-Lymphocyte↗
PubMed1987

Intracellular reovirus survives cytotoxic T lymphocyte-mediated lysis of its host cell.

Cytotoxic T lymphocytes (CTLs) induce rapid, extensive internal disintegration in target cells and this is unique among immune lytic mechanisms studied. This raises the question of whether CTLs are uniquely capable of halting virus infections by inducing damage within the target cell causing inactivation of intracellular virus. Reovirus infection of mouse P815 cells provided a suitable system for evaluating this question. An increase in cell-associated infectious virions began 8 h after infection and increased until 20 h post-infection, at which time the titre levelled off at about 100- to 1000-fold higher than the initial value. The infectious activity was compared between host cells killed by CTLs and those killed by sonication at various points in the infection cycle. The presence of reovirus within the target cell did not inhibit the usual internal disintegration events associated with the death of a target killed by CTLs. Nevertheless, the results indicated that CTLs were incapable of inactivating intracellular reovirus at any point in the life cycle of the virus: CTL-induced cytolysis simply released the infectious virions into the medium. Thus, at least in the case of reovirus, the utility of direct killing by CTLs would appear to be limited to reduction of the virus yield by lysis of the host cell before virus replication and assembly is completed.

Animals↗
PubMed1985

Lymphocyte function-associated antigens: regulation of lymphocyte adhesions in vitro and immunity in vivo.

Antibodies to most cytolytic T lymphocyte (CTL) external membrane antigens have no effect on CTL-mediated killing in the absence of complement. However, antibodies which do inhibit killing have now been identified for 7 distinct molecular sites. Antibodies to 6 of these "lymphocyte function-associated antigens" (LFAs, also called "blocking sites") inhibit when bound to the CTL, and to the 7th, when bound to the target cell. Mouse homologs have been identified for only 4 of the 7 human LFAs. 5 (probably 6) of the blocking sites inhibit by interfering with adhesion formation between the CTL and the target cell; the exception is T3. None of the presently identified blocking sites are believed to be lethal hit structures (CTL "toxin"). Reduction of target cell H-2 alloantigen density by pretreatment with papain reduces CTL-target functional "affinity", and increases susceptibility to inhibition 100-fold for anti-Lyt-2,3 and 10-fold for anti-LFA-1. This is consistent with the hypothesis that Lyt-2,3 aids in recognition of class 1 MHC antigens, perhaps by strengthening intercellular adhesion. On the other hand, LFA-1 appears to function differently. Trypsin pretreatment of target cells has little effect on MHC antigens or CTL-target affinity, yet still increases by 10-fold susceptibility to inhibition by anti-LFA-1. This is seen in both human and mouse CTL systems. These results suggest the existence of a non-MHC target structure which participates in the adhesion-strengthening function of LFA-1, and which is trypsin (and papain) sensitive: the "trypsin-sensitive counter blocker" (TSCB). LFA-3 may be the human TSCB. The roles of these LFAs in intercellular adhesion extend to more general cell adhesions. Anti-LFA-1 and anti-LFA-3 weaken the spontaneous adhesions which form between cells of the human B cell line JY. These homotypic adhesions are not initiated by immunologic recognition. Anti-LFA-1 is more potent at prolonging allograft survival in vivo than are anti-Lyt-2,3, anti-T200, anti-Thy-1, or anti-I-A. Thus, the potent anti-adhesion properties of LFA-1 seen in vitro may lead to useful immunotherapy in the clinic.

Animals↗
PubMed1985

Functional distinctions between the LFA-1, LFA-2, and LFA-3 membrane proteins on human CTL are revealed with trypsin-pretreated target cells.

We asked whether we could distinguish the roles of the human lymphocyte membrane proteins LFA-1, LFA-2, and LFA-3 in the function of CTL-mediated killing. Little is known about the functions of these molecularly distinct proteins beyond the facts that i) binding of a monoclonal antibody (MAb) to any one of them is sufficient to inhibit killing, ii) that in each case inhibition involves prevention of CTL-target cell conjugate formation, and iii) that MAb to LFA-1 and LFA-2 inhibit best when bound to the CTL, whereas anti-LFA-3 inhibits only when bound to the target cell. This latter is despite the fact that (in our test system) LFA-1 and LFA-3 are expressed both on the CTL and on the target. When the target cells were pretreated with trypsin, the sensitivity of CTL-mediated killing was affected in a different way for each site. Inhibition of anti-LFA-1 was increased by approximately 20-fold. Inhibition by anti-LFA-2 was unaffected. Inhibition by anti-LFA-3 was abolished. Trypsin did not remove the specific antigens recognized by the various CTL, HLA-A,B,C or HLA-DR. Nor did it remove LFA-1 from the target cell. It did, however, selectively remove LFA-3 from the target cell. These results indicate, for the first time, that LFA-1 and LFA-2 have functionally distinct roles. They suggest that an unidentified trypsin-sensitive target cell molecule, operationally designated the "trypsin-sensitive counter blocker" (TSCB), plays an important role in the function of LFA-1, possibly by providing a target cell binding site for LFA-1 on the CTL. The hypothesis that this TSCB is identical to LFA-3 (and the related possibility that LFA-1 and LFA-3 are mutual ligands) is not favored by our data, but is not excluded. Finally, the data indicate that the mechanisms by which MAb inhibit killing differ at the LFA-1 and LFA-3 sites. They are consistent with LFA-1 providing adhesion strengthening by binding to another site (the TSCB?) and with LFA-3 delivering an inhibitory signal when provoked with MAb.

Antibodies, Monoclonal↗
PubMed1985

Blocking of CTL-mediated killing by monoclonal antibodies to LFA-1 and Lyt-2, 3. II. Evidence that trypsin pretreatment of target cells removes a non-H-2 molecule important in killing.

We sought additional evidence for an inverse relationship between functional CTL-target cell affinity on the one hand, and susceptibility of the CTL-mediated killing to inhibition by alpha LFA-1 and alpha Lyt-2,3 monoclonal antibodies on the other hand. Previously, we experimentally reduced affinity by pretreating the target cells with papain. This removed most of the class I H-2 antigens, had little effect on the ability of allospecific CTL to recognize and kill these targets, but dramatically reduced the initial strength of CTL-target cell adhesion, and increased by more than 10-fold the susceptibility of the killing to inhibition by alpha Lyt-2,3 and alpha LFA-1 MAb. In the present report, we find that pretreating the target cells with trypsin, like papain, does not significantly change the susceptibility of the target cells to killing by allospecific CTL in a 2-hr assay, and increases by about 10-fold susceptibility of the killing to inhibition by alpha LFA-1. Unlike papain, however, trypsin does not consistently increase blocking by alpha Lyt-2,3, does not remove class I H-2 antigens from the target cell, and does not substantially reduce the strength of initial CTL-target adhesion formation (estimated by post dispersion lysis after a 5-min conjugate-forming incubation). These results show a functional difference between LFA-1 and Lyt-2,3. Both papain and trypsin produced similar 10-fold increases in susceptibility to blocking by alpha LFA-1. In contrast, susceptibility to inhibition by alpha Lyt-2,3 was increased nearly 100-fold by papain, but was not consistently affected by trypsin. Thus, the above-mentioned inverse relationship holds for alpha Lyt-2,3 but not for alpha LFA-1. Our results are consistent with the hypothesis that Lyt-2,3 but not LFA-1 participates in recognition of class I H-2 antigens. Possibly LFA-1 participates in an adhesion-strengthening process that follows T cell recognition, and which may also be used by other LFA-1 expressing leucocytes in intercellular interactions. Finally, our results suggest (for the first time in the mouse system) that an unidentified non-H-2 "trypsin-sensitive counter blocking" molecule on the target cell plays an important role in CTL-target cell interaction.

Animals↗
PubMed1985

LFA-1 membrane molecule in the regulation of homotypic adhesions of human B lymphocytes.

We report here that MAb to human LFA-1 inhibit spontaneous homotypic adhesions of human B lymphocytes. This is, to our knowledge, the first report of a MAb that inhibits human homotypic intercellular adhesions for any cell type. LFA-1 has previously been recognized as a molecule capable of regulating specific immunologic adhesions between T lymphocytes and antigen-bearing target cells. The present findings show that the role of LFA-1 is not limited to adhesions initiated by specific immunologic recognition. The results indicate that the LFA-1 molecule is capable of regulating lymphocyte adhesions, possibly because it is a direct participant in adhesion formation.

Animals↗
PubMed1983

Blocking of CTL-mediated killing by monoclonal antibodies to LFA-1 and LYT-2,3. I. Increased susceptibility to blocking after papain treatment of target cells.

It is now established that monoclonal antibodies (MAb) against LFA-1 and Lyt-2,3 antigens on cytolytic T lymphocytes (CTL) block killing function in the absence of C. It has been suggested that the blocking is inversely related to CTL-target affinity. In this report, we studied the effect of papain pretreatment of target cells, because papain is known to remove H-2 and to render target cells more resistant to allospecific CTL. CTL-target conjugate formation was weaker with papain-treated target cells (based on reduced post-dispersion lysis in dextran-containing medium). The concentration of MAb required to produce 40 to 60% inhibition of 51Cr release (2-hr assay) was reduced four to 29-fold for alpha LFA-1 and 64 to 114-fold for alpha Lyt-2,3. Papain, however, did not induce blocking by MAb to other CTL antigens such as Thy-1, H-2, and T200. Flow cytometric analysis confirmed that papain selectively removed more than 95% of H-2. In kinetic studies of removal and recovery, H-2 density and conjugate formation correlated well with each other. Sensitivity to blocking was not as well correlated, raising the possibility that an unidentified papain-sensitive target cell molecule other than H-2 plays an important role in CTL-target interaction.

Animals↗
PubMed1982

The molecular basis for cytolytic T lymphocyte function: analysis with blocking monoclonal antibodies.

During the past decade the mechanism of CTL-mediated killing has been resolved into 3 steps, and its cation requirements, and general nature have been well defined. However, biochemical understanding of the CTL-target interaction has made little progress. Recently, we have developed a monoclonal antibody (MAb) which blocks killing by binding to a previously undescribed molecule on the CTL membrane, a molecule which we therefore have termed lymphocyte function-associated antigen one (LFA-1). LFA-1 and Lyt-2,3 are the only presently identified sites for such blocking; antibodies to over a dozen other molecules expressed on the CTL do not block killing. Present evidence suggests that LFA-1 is crucial in the adhesive interaction of T cells with other cells (e.g., targets, macrophages, perhaps B cells) The continuing search for blocking MAbs provides a systematic way to link specific molecules with CTL function.

Animals↗