Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The H-2da haplotype was derived from the H-2d haplotype by a mutation localized to the D end of the H-2 complex. Coculture of H-2d and H-2da spleen cells gives rise to bidirectional MLR. However, the H-2d anti-H-2da response is much stronger than that of H-2da anti-H-2d. Both haplotypes give rise to reciprocal CML. B10.D2(R103) strain spleen cells, which differ only at the D end of the H-2 complex from the H-2d haplotype, kill H-2da target cells in CML when sensitized to H-2d stimulators and vice versa. Therefore, both the mutant and strain of origin share a D end CML specificity. H-2d and H-2da reject skin grafts in both directions, although some H-2d grafts show prolonged acceptance on H-2da recipients. These data are consistent with a mutation in the D end of the H-2d haplotype resulting in gain-loss of an antigen(s) that gives rise to reciprocal MLR, CML, and skin graft rejection. Further, the mutant can be distinguished from the strain of origin on the basis of the strength of immune response in MLR.
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PMID:Immunogeneic analysis of H-2 mutations. II. Cellular immunity to the H-2DA mutation. 12

T-cell tolerance to CML and MLR determinants in tetraparental bone marrow chimeras, prepared by injecting lethally x-irradiated F1 hybrids with bone marrow cells from both parental strains, is most likely due to clonal deletion. Tolerance to CML, but not to the host's MLR, determinants is observed when lethally x-irradiated F1 hybrids are repopulated with bone marrow from one parental strain only. The results demonstrate that removal of T cells from donor cells, as well as exclusion of a HVG reaction, make it possible to transplant bone marrow between allogeneic individuals.
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PMID:Hemopoietic reconstitution obtained in F1 hybrids by grafting of parental marrow cells. 13 73

Two antigen-nonspecific T cell-dependent suppressor systems were compared for their effects upon CML and MLR. Suppressor cells generated by an in vitro culture of spleen cells were compared with suppressor cells generated by in vivo priming with alloantigen. Culture-induced suppressor cells were themselves unable to respond in CML or MLR; were able to suppress actively the CML and MLR responses of untreated responding cells; were mitomycin-sensitive; and, produced no easily demonstrable suppressive supernatant. Alloantigen-primed cells were able to respond in CML and LR; could suppress proliferation in MLR, but were able to suppress CML only after mitomycin treatment; and, produced suppressive supernatants active in suppressing both CML and MLR. In addition to cataloging the differences and similarities between these suppressor populations, the data have been employed to analyze the mechanisms by which suppression occurs in CML and MLR.
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PMID:Regulatory mechanisms in cell-mediated immune responses. II. Comparison of culture-induced and alloantigen-induced suppressor cells in MLR and CML. 14 Jan 97

The effect of deoxymethylspergualin (MeDSG) on in vitro human lymphocyte response was assessed in comparison with FK506 and cyclosporine. Peripheral blood mononuclear cells from normal human volunteers were used for assay of mixed lymphocyte reaction, cell mediated lympholysis, and blastogenesis by PHA, IL-2, and OKT3. MeDSG suppressed only allogeneic stimulation (MLR and CML) and IL-2-induced blastogenesis, not PHA- or OKT3-induced blastogenesis, although the other immunosuppressive agents showed some suppressive effect for all assays. A kinetic study of MLR showed that the suppressive activity did not decrease even when MeDSG was added at day 3 or day 4. The other agents, however, showed a weak suppressive effect when added at a later phase of MLR.
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PMID:The in vitro immunosuppressive effect of deoxymethylspergualin in man as compared with FK506 and cyclosporine. 137 37

Partially inbred, MHC-homozygous miniature swine provide a unique model for the study of organ transplantation and the induction of tolerance in large animals. Models of both vascularized solid organ transplantation and bone marrow transplantation have previously been established. The availability of monoclonal antibodies reactive with porcine leukocyte subset antigens now makes possible studies of the cellular immunology in this species, affording the opportunity to examine mechanisms of transplant tolerance and graft rejection in increasing detail. Using such antibodies and peripheral blood leukocytes from pigs of recombinant MHC haplotypes, we have examined porcine T cell-accessory cell interactions in vitro with attention to T cell subsets and the class of MHC alloantigen stimulation. Primary allospecific MLR and CML cultures were studied after depletion of accessory cells from responder and/or stimulator populations. Although class II MHC antigens were expressed on the majority of porcine T cells before and after depletion, these cells were insufficient for antigen presentation, since there was an absolute requirement for ACs in the generation of primary alloresponses. Proliferative and CTL alloresponses could be generated provided that ACs of either stimulator or responder type were present. Selective depletion of CD4+ T cells from the responder population demonstrated: (a) that the interaction mediated by self ACs was CD4-dependent; (b) that two pathways exist for interaction involving allogeneic ACs; and (c) that the interaction involving allogeneic class II is CD4-dependent, while that with allogeneic class I is not.
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PMID:Patterns of T cell-accessory cell interaction in the generation of primary alloresponses in the pig. 144 Aug 58

FK506 is an unusually potent new immunosuppressive agent that inhibits T cell-mediated immunity in vivo and in vitro. In these studies we sought to further elucidate the immunosuppressive mechanism of action of FK506 on human allogeneic MLR-induced CTL activation. FK506 induced suppression of cell-mediated lympholysis by PBMC was optimal at 1-2-nM concentrations, if added at the initiation of 6 day CML cultures. The sensitivity to suppression decreased with time, and fully differentiated effectors were resistant to inhibition by FK506. Suppression of CML was not reversed by washing the cultures, adding exogenous IL-2, or restimulating with fresh cells. Pretreatment of unfractionated or adherent allogeneic PBMC with FK506 blocked the stimulating activity of these cells. Furthermore, addition of FK506-treated stimulator cells to cocultures containing untreated responder and stimulator cells resulted in suppression of CML. The inhibition in the cocultures was greatest if the FK506-pretreated cells were autologous to the original stimulator, suggesting a relative specificity in the suppression obtained under these conditions. These studies suggest that, in addition to suppressing the response of alloreactive CTL precursors, FK506 reduces the ability of irradiated allogeneic PBMC to induce CTL generation.
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PMID:The immunosuppressive action of FK506. In vitro induction of allogeneic unresponsiveness in human CTL precursors. 168 18

Long-term specific tolerance to one haplotype class I plus minor antigen disparate renal allografts develops without exogenous immunosuppression in approximately 35% of miniature swine (n = 128). Previous studies have suggested that this phenomenon is related to limited class I-specific helper T cell activity as evidenced by the failure of antibody class switching in vivo and the ability of exogenous interleukin 2 to elicit antidonor responses in vitro. To determine whether tolerance could be broken by inducing antidonor reactivity with donor antigen and a source of T cell help, multiple skin grafts bearing donor class I plus third-party class II antigens were placed on tolerant animals. Skin grafts were placed at least 3 months after the kidney transplant, at which time all recipients had normal renal function as measured by blood urea nitrogen and serum creatinine. First-set rejection of skin grafts by SLAad and SLAdd hosts occurred in 11.8 +/- 1.1 days (mean +/- SEM, n = 6) and in 9.3 +/- 0.9 days (n = 4), respectively. Coincident with skin rejection, most animals developed a transient rise in BUN to 62 +/- 11 mg/dl (n = 10) and a similar rise in Cr to 4.9 +/- 1.2 mg/dl (n = 10), with normal levels returning in all animals within two weeks. Subsequent skin grafts with the same disparity did not undergo second-set rejection and did not induce BUN or Cr elevations. Prior to skin grafting, animals showed no antidonor activity in mixed lymphocyte reaction or cell-mediated lymphocytotoxicity assays. After two skin grafts, all animals developed donor-specific CML and secondary MLR responses, and additional skin grafts amplified this cellular immunity. Development of marked antidonor immunity without a break in tolerance suggested that either graft adaptation or local suppression might be involved in maintaining tolerance to class I MHC antigens. In preliminary studies, an immunized SLAad animal and an immunized SLAdd animal were retransplanted with kidneys MHC matched to their first allografts. In both cases, the second graft was accepted permanently without immunosuppression, suggesting that graft adaptation is not necessary for the maintenance of tolerance to renal allografts in miniature swine.
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PMID:The failure of skin grafting to break tolerance to class I-disparate renal allografts in miniature swine despite inducing marked antidonor cellular immunity. 175 67

Placental adherent cells (PAC), derived by mild enzymic digestion of human placentae and adherence to plastic, were tested for their ability to suppress MLR and CML reactions. Stimulation of allogeneic T cells by cord blood mononuclear cells or by a strongly stimulatory B lymphoblastoid cell line were consistently inhibited by all PAC preparations tested. PAC were fractionated by Fc rosetting and Percoll gradients to produce a number of bands. Suppression correlated with the content of macrophages in each band and was strongest in band 5 which generally contained 94-100% macrophages. The suppressive effect was not inhibited by indomethacin. The possible role of macrophages in suppressing immune reactivity in the placenta is discussed.
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PMID:Class II MHC antigen-positive macrophages from human placentae suppress strong MLR and CML reactions. 213 19

Supernatants were prepared from short-duration explant cultures of term human placentas obtained after cesarean delivery. These supernatants inhibited murine and human mixed lymphocyte reactions, as well as CTL generation. The effects were reversed by an excess of IL-2-containing medium. Similarly, the material inhibited human natural killer cytotoxicity against K 562 targets. The material was subjected to gel-filtration chromatography on an ACA 44 or Bio-Gel A15m column. The apparent MW of the MLR-CML material was about 60-70 kDa, whereas the NK inhibiting activity was eluted in high-MW components (greater than 200 kDa) as well as in the 50-kDa range. The relevance of this material in local immunoregulation during human pregnancy is discussed.
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PMID:Immunoactive products of human placenta. I. An immunoregulatory factor obtained from explant cultures of human placenta inhibits CTL generation and cytotoxic effector activity. 252 22

Since tolerogen-specific helper activity is present in MLR-positive class II MHC tolerant mice, a loss of helper activity is unlikely to be responsible for the maintenance of tolerance in these mice. An alternative hypothesis, that effector cell function is selectively down-regulated, has been examined with lymphocytes from MLR-positive class-II MHC tolerant mice on both the A strain and the B10 background. The results demonstrate that lymphocytes from A-strain-tolerant mice were unable to generate tolerogen-specific effector cells in any of the assays tested (CML with or without exogenous growth factor and DTH following in vivo priming or local adoptive transfer), even though these mice possess tolerogen-responsive T helper cells. In contrast, a majority of MLR-positive tolerant mice on the B10 background generated measurable tolerogen-specific cytotoxic activity in the absence of exogenous growth factor, and all the mice examined generated substantial cytotoxic activity in the presence of exogenous growth factor. However, in a local adoptive transfer reaction, lymphocytes from these mice failed to display DTH. It is concluded that tolerance is maintained by selective impairment of class II specific effector functions and that regulation of DTH rather than CTL activity may be central to maintenance of in vivo tolerance to class II MHC antigens.
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PMID:Differential expression of helper versus effector activity in mice rendered neonatally tolerant of class II MHC antigens. 252 2


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