Biomedical subjects

M K Jenkins

Publications and source records attributed to M K Jenkins.

81 records · Page 5Linked to original sources

PubMed1987

In vitro and in vivo correlates of hybrid tumor resistance.

Tumorigenicity of 2 sublines, TU1 and TM5, of the C.B6-H-2dm4 (dm4) mouse tumor, TDM4, was tested in dm4 and F1 hybrid mice (from crosses of dm4 with a variety of other strains) to determine the genetics of hybrid resistance to these 2 tumor sublines. Resistance to TU1 was associated with at least 3 genes and required heterozygosity in the H-2D region, with secondary effects attributable to H-2K genes and non-H-2 genes. Resistance to TM5, however, did not require H-2D region heterozygosity, whereas H-2K and non-H-2 genes appeared to have significant effects. For evaluation of possible mechanisms for hybrid resistance, 4 assay systems were used. Comparison of natural killer cell activity in dm4 and various hybrid mice revealed no consistent activity against either TU1 or TM5. Little correlation was seen between resistance and generation of strong T-lymphocyte proliferative responses to the sublines. Likewise, cytotoxic T-lymphocyte (CTL) activity, particularly against TU1, was not associated with increased resistance. In contrast, delayed-type hypersensitivity (DTH) was consistently greater in hybrids with increased resistance to either subline. These results suggest a strong association between DTH responsiveness and hybrid resistance. Furthermore, the association, in some hybrids, of CTL activity with resistance to the TM5 subline, but not to TU1, may mean that different sublines of the same tumor can induce different sets of immune responses.

Animals↗

PubMed1986

Suppressor T cell circuits in contact sensitivity. III. A monoclonal T cell hybrid-derived suppressor factor specifically suppresses local DTH transfer by a DNP-specific T cell clone.

Herein we described the direct suppressive effects of a monoclonal T cell hybridoma-derived, DNP-specific suppressor T cell factor (26.10.2 TsF) on the local transfer of delayed-type hypersensitivity (DTH) by a DNP-specific BALB/c T cell clone (dD1.9). The L3T4+, Lyt-2- dD1.9 T cell clone proliferated in response to DNP-OVA and DNBS, but not TNP-OVA or TNBS, in association with I-Ed determinants present on antigen-presenting cells. Similarly, local injection of histopaque-purified dD1.9 cell blasts resulted in DNP-specific, radioresistant, I-Ed-restricted, mononuclear cell-rich ear swelling responses. Incubation in 26.10.2 TsF specifically suppressed local transfer of DNP-specific DTH by dD1.9, but not local DTH responses transferred by BALB/c T cell clones specific for TNP or GAT. The suppressive effect of 26.10.2 TsF correlated with targeting on DNP-major histocompatibility complex determinants associated with the DTH T cell (TDH) targets. 26.10.2 TsF-mediated suppression was most pronounced after exposure of dD1.9 target cells to antigen (after the stimulation phase of the T cell clone maintenance procedure), and greatly reduced when dD1.9 was cultured for long periods in the absence of DNP (after the rest phase of clone maintenance). In additional support of this hypothesis, GAT-specific TDH, normally resistant to 26.10.2 TsF-mediated suppression, were rendered susceptible to suppression after surface DNPylation. The results demonstrate a direct, antigen-specific, effector phase regulatory effect of a monoclonal TsF on a cloned, antigen-specific T cell target, and strongly suggest that suppression is mediated via targeting on DNP determinants associated with the TDH target. Simplification of complex Ts circuitry operating in suppression of the efferent limb of DTH by the use of monoclonal TsF and cloned T cell targets should provide a basis for the future study of the molecular mechanisms of immune suppression.

Animals↗

PubMed1986

Mechanisms of genetic control of immune responses. II. Nonresponsiveness in BALB/c GT-specific cell-mediated immune responses does not correlate with the absence of functional T cells or the induction of suppressor T cells.

The mechanisms underlying Ir gene control of CMI were addressed by examining the DTH and Tprlf responses specific for the synthetic polymers GT, GAT, and GA. We show that BALB/c mice (GAT/GA responders, GT nonresponders) primed with GT fail to develop DTH and Tprlf responses specific for GT, GAT, or GA. GAT immunization resulted in DTH responses that could be elicited not only with GAT and GA but also with GT, demonstrating that GT-specific TDH are present in nonresponder mice. GT-specific DTH was transferred with Thy-1+ Lyt-1+2-, H-2 I-restricted, nylon wool nonadherent cells. GA-primed BALB/c mice developed GAT- and GA-, but not GT-specific DTH responses, indicating that GA and GT do not cross-react at the T-cell level. The ability of GAT [but not a mixture of GA plus GT, or GT electrostatically complexed to the immunogenic carrier MBSA (GT-MBSA)] to induce GT-specific DTH suggested a requirement for covalent linkage of stimulatory 'GA' and nonstimulatory 'GT' determinants present on the GAT molecule. Similarly, GT-specific in vitro Tprlf responses could be demonstrated in GAT-primed mice exhibiting significant levels of GT-specific DTH but not in GT- or GT-MBSA-primed mice. Tolerization experiments also suggested that GT-specific Th were involved in the development of GT-specific DTH in GAT-primed mice. The GT nonresponsiveness of BALB/c mice for DTH and Tprlf responses could not be reversed by treatments designed to abrogate Ts activity (priming with GT-MBSA and CY injection), nor could GT-primed cells be shown to inhibit the development or elicitation of GT-specific CMI in GAT-primed mice during the afferent and/or efferent stages of DTH. Our results suggest that GT nonresponsiveness does not result from the absence of GT-specific T cells or preferential induction of Ts. The results are discussed in the context of hole-in-the-repertoire and antigen presentation (determinant selection) models of Ir gene control.

Alanine↗

PubMed1985

In vivo effects of GK1.5 (anti-L3T4a) monoclonal antibody on induction and expression of delayed-type hypersensitivity.

The in vivo effects of monoclonal GK1.5 antibody, directed against the L3T4a determinant expressed on Class II-restricted T cells, on the induction and expression of murine delayed-type hypersensitivity (DTH) responses were examined. Development and expression of both hapten (2,4-dinitrofluorobenzene and 2,4,6-trinitrochlorobenzene)- and protein antigen poly(Glu60Ala30Tyr10)-specific DTH are significantly inhibited by injection of monoclonal anti-L3T4a antibody. The inhibitory effects of anti-L3T4a were most pronounced when administered during the afferent (induction) phase of the DTH response, leading to the functional inhibition of the generation of both polyclonal lymph node T-proliferative cells (Tprlf) and DTH effector cells (TDH). The in vivo inhibitory effect is apparently unrelated to preferential induction of suppressor T cells as GK1.5 inhibited DTH induction in cyclophosphamide-treated as well as normal recipients. L3T4a expression on the various T-cell subsets involved in DTH induction and elicitation was also examined. The data show that three functionally distinct, antigen-specific T-cell subsets, Tprlf, TDH, and Th cells involved in DTH induction, bear the Lyt 1+2-, L3T4+ phenotype. Possible mechanisms where in vivo injection of anti-L3T4a inhibits Class II-restricted T-cell subsets involved in DTH induction and expression, including immune depletion and inhibition of T-cell-receptor/ligand interactions, are discussed.

Animals↗

PubMed1985

Immunoregulatory pathways in adult responder mice. III. Establishment of a GAT-specific suppressor T cell clone from GAT-tolerant responders which afferently regulates DTH responses.

Recent advances in the biochemical and genetic analysis of soluble immunoregulatory molecules (TsF) have been achieved via the establishment of cloned TsF-producing T cell hybridomas. However, studies on in vivo regulation of immune responses have been hampered by the lack of clonal populations of nontransformed suppressor T cells (Ts). Nonhybridoma Ts clones would allow cellular dissection of complex Ts circuits and precise analyses of Ts effector mechanisms. Our laboratory has recently demonstrated that poly(Glu60Ala30Tyr10) (GAT)-specific unresponsiveness is induced in adult responder mice tolerized via the intravenous injection of GAT-coupled syngeneic spleen cells (GAT-SP). This unresponsiveness is mediated by two antigen-specific mechanisms--nontransferable clone inhibition and induction of transferable Ts which regulate both humoral and T cell-mediated delayed-type hypersensitivity (DTH) responses. We have thus applied methodology used for the production and maintenance of antigen-specific T helper (Th) clones in an attempt to establish and characterize Ts clones mediating GAT-specific in vivo suppressive activity. Therefore, spleen cells from GAT-SP tolerant responder mice were maintained in continuous culture with soluble GAT, 10% concanavalin A-conditioned medium (IL-2), and irradiated syngeneic antigen presenting cells (APC). A stable, long-term Ts cell line (J372) was isolated by this procedure. This line and one of its clones (J372.2) suppressed the afferent (induction), but not efferent (elicitation) phase of GAT-specific DTH. In contrast, the J372.2 Ts clone had no inhibitory effect on the development of specific T cell proliferative responses. Intravenous injection of small numbers (2-5 x 10(6)) of J372.2 Ts cells resulted in significant suppression of DTH responses in GAT-primed, but not in ovalbumin- or methylated bovine serum albumin-primed recipients, demonstrating the antigen-specificity of the suppression. Intravenous injection of a GAT-specific Th clone (JTL-E1) or of a DNP-specific Th line (JTL-DNP) had no suppressive effects on GAT-specific responses suggesting that J372.2-mediated unresponsiveness is the result of active suppression, and not the result of nonspecific inhibitory effects of activated T cells. More importantly, normal GAT-specific DTH responses in recipients of the JTL-E1 Th clone (maintained in the same GAT concentration as J372.2) indicated that J372.2-mediated suppression was not due to induction of nontransferable tolerance by surface-associated GAT.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1985

Immunoregulatory pathways in adult responder mice. II. Regulation of delayed-type hypersensitivity responses by GAT-specific suppressor factors present in GAT-tolerant adult responder mice.

We studied the effects of T cell extracts from adult responder BALB/c mice tolerized with poly(Glu60Ala30Tyr10) (GAT)-coupled syngeneic spleen cells (GAT-SP) on delayed-type hypersensitivity (DTH), T cell-proliferative (Tprlf), and plaque-forming cell (PFC) responses. Adult responder mice injected i.v. with GAT-SP develop Lyt-1-2+ suppressor T cells (Ts), which suppress the induction of GAT-specific DTH and PFC, but not Tprlf responses. Sonicates from these Ts contain an afferent-acting, soluble factor(s) (GAT-TsFdh) that specifically suppresses the same responses as the intact Ts (i.e., DTH and PFC, but not Tprlf). Immunosorbent chromatography studies were employed to determine the molecular nature of the suppressive material active on both cellular and humoral responses. In both assay systems, GAT-TsFdh was found to bear determinants encoded by the I subregion of the H-2 complex and a receptor(s) for GAT. BALB/c-derived GAT-TsFdh suppressed the induction of GAT DTH in syngeneic BALB/c and H-2-compatible B10.D2, but not in allogeneic C57BL/6 or CBA/Cum, suggesting a possible H-2 restriction in the suppression. It was also shown that one target of functional regulation by GAT-TsFdh is the T helper cell for DTH responses (DTH-Th). The results suggest that similar Ts and TsF regulate humoral and cell-mediated responses, perhaps by affecting a target common to both pathways (e.g., the T helper cell). The resistance of Tprlf responses to suppression by GAT-TsFdh indicates that the effector DTH-Th target is not a major component of the proliferative response. These data are discussed with respect to GAT-specific TsF-regulating PFC responses, which have been identified in nonresponders and in responders tolerized as neonates with GAT.

Animals↗

PubMed1984

Immunoregulatory pathways in adult responder mice. I. Induction of GAT-specific tolerance and suppressor T cells for cellular and humoral responses.

This report describes the alteration of helper-suppressor balances in an immune response (Ir) gene-controlled system by varying the route and form of antigen injection. Adult responder BALB/c mice develop Lyt 1+2-, T cells for delayed-type hypersensitivity (DTH), and T-cell proliferative (Tprlf) responses to subcutaneous injection of either poly(Glu60Ala30Tyr10) (GAT)-coupled syngeneic spleen cells (GAT-SP) or GAT emulsified in complete Freund's adjuvant. In contrast, intravenous injection of adult responders with GAT-SP results in specific unresponsiveness for DTH, Tprlf, interleukin-2, and plaque-forming cell (PFC) responses. This tolerance is mediated by both suppressor T cells (Ts) and a functional clonal inhibition. Lyt 1-2+ Ts suppress the induction (afferent limb) of GAT-specific DTH and PFC but not Tprlf responses. The reduced T-cell proliferation observed in GAT-tolerant mice is due to a non-transferable mechanism(s), possibly functional clonal inhibition. Our data are compatible with a multi-step pathway involving both proliferating and non-proliferating helper T (Th) cells. In addition, the fine specificity of tolerance induction for DTH and Tprlf responses was examined by using the related antigens poly(Glu60Ala40) (GA) and poly(Glu50Tyr50) (GT). Tolerance is exquisitely specific, as GA tolerizes responses to GA and GAT, whereas GT tolerizes GAT but not GA responses. Thus, both the route and form of antigen administration are important to the induction and regulation of immune response in Ir gene-controlled systems. Possible mechanisms governing the Th/Ts balance and the induction of GAT-specific tolerance and suppression for cellular and humoral responses in adult responders are discussed.

Animals↗

PubMed1984

Isolation and characterization of an I-A-restricted T cell clone with dual specificity for poly(Glu60Ala30Tyr10) (GAT) and Mlsa,dl.

We have isolated a BALB/c (H-2d, Mlsb) T cell clone (JTL-G12) specific for the synthetic polypeptide antigen poly(Glu60Ala30Tyr10) (GAT) in the context of self I-A determinants and for Mlsa,d antigens in the absence of GAT. JTL-G12 proliferation in response to GAT was mapped to the Kd, I-Ad subregions by using inbred H-2 congenic and recombinant strains. In addition, monoclonal antibody directed against I-Ad but not Kd or I-As determinants blocked JTL-G12 proliferation in response to GAT presented by syngeneic splenocytes, indicating I-A restriction. The Mls cross-reactivity of this clone was verified by using a panel of inbred strains bearing the Mlsa,b,c,d alleles and by using BXD recombinant inbred strains bearing the Mlsa allele or the Mlsb allele. All of the Mlsa BXD strains of the H-2d or H-2b haplotypes stimulated JTL-G12 in the absence of GAT, whereas all of the Mlsb BXD strains were nonstimulatory. This response pattern is in complete accordance with recognition of the Mlsa determinant encoded by Mls or closely linked loci on chromosome 1. JTL-G12 proliferation in response to GAT/I-Ad and Mlsa,d determinants could be blocked with a monoclonal antibody (GK1.5) directed against L3T4, a structure involved in class II major histocompatibility complex antigen recognition. These results suggest that antigen/class II responsiveness, Mls reactivity, and expression of L3T4 can be properties of a single T cell population.

Animals↗

PubMed1981

Neutrophil dysfunction in sepsis. II. Evidence for the role of complement activation products in cellular deactivation.

Abnormalities in chemotactic and bactericidal activity have been identified in patients suffering from burn injury, trauma, and infection. Such abnormalities may lead to bacteremia or nosocomial infection. The mechanism for these abnormalities is unclear. We studied the role of chemotactic deactivation by complement component C5a in 47 patients with intra-abdominal infection and with disordered neutrophil function. Plasma C5a levels in such patients were elevated (102.1 +/- 8.3 versus 52.6 +/- 3.4 ng/ml for control subjects, P less than 0.01). There was a linear relationship between C5a and chemotaxis (r = 0.56, P less than 0.01). Examination of patients' neutrophils showed changes consistent with nonspecific deactivation. There were parallel losses of chemotaxis to N-formyl methionyl-leucyl-phenylalanine (FMLP) and activated serum (C5a) (r = 0.74, P less than 0.001), chemotaxis and intracellular beta-glucuronidase (r = 0.82, P less than 0.001), and C5a and FMLP chemotaxis and (r = 0.56, P less than 0.01). Receptor assays revealed specific loss of C5a binding but intact FMLP binding. Exposure of normal neutrophils to plasma from patients with depressed chemotaxis caused similar loss of C5a receptors and loss of FMLP and activated serum-induced chemotaxis at high plasma concentrations and selective loss of activated serum response at lower concentrations. These data support the concept that a major factor leading to neutrophil dysfunction during intra-abdominal infection is nonspecific chemotactic deactivation of neutrophils after in vivo exposure to high levels of chemoattractants such as C5a.

Adolescent↗