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Biomedical subjects

A M van Dijk

Publications and source records attributed to A M van Dijk.

14 recordsLinked to original sources
PubMed2000

Determination of helper T-cell precursor frequencies against non-haemopoietic cells: comparison of co-stimulation provided by anti-CD28 antibody versus the cellular ligand B7-1.

Helper T-cell precursor frequency assays (HTLp-assays) are commonly used in transplantation to examine the frequency of T cells reactive against donor or host alloantigens. In these assays, peripheral blood mononuclear cells (PBMCs) are most often used as stimulator cells. However, cells targeted after transplantation do not always belong to the haematopoietic lineage and may express different alloantigens, especially minor histocompatibility antigens (mHags). Non-haematopoietic cells lack expression of the B7 co-stimulatory molecules needed to activate primary T cells that can be supplied by anti-CD28 (alphaCD28) antibodies or transfection with B7-1 coding sequences. At present, it is not known how these two ways of supplied co-stimulation compare in HTLp assays. B7-1-transfected A431 keratinocytes (A431B7-1) induced higher proliferative responses in allogeneic primary T cells and more interleukin (IL) 2 production than that induced by A431 cells plus alphaCD28, whereas the kinetics of proliferation and IL-2 production were similar. Neither cross-linking of alphaCD28 bound to T cells nor prevention of IL-2 resorption by the anti-IL-2 receptor resulted in improved proliferation or IL-2 production. Results of HTLp assays indicated that A431B7-1 activated on average 7.5 times more alloreactive IL-2-producing T cells than A431 cells plus alphaCD28. We conclude that primary T-cell alloresponses against major histocompatibility complexes (MHCs) and mHags expressed on non-haematopoietic cells can be measured in HTLp assays using supplied co-stimulation, although alphaCD28 yields an intrinsic underestimation of actual frequencies.

Antibodies, Monoclonal↗
PubMed2000

Primary human keratinocytes as targets in predicting acute graft-versus-host disease following HLA-identical bone marrow transplantation.

Graft-versus-host-disease (GVHD) remains a major problem following allogeneic bone marrow transplantation (BMT) and manifests itself mainly by damage to epithelial cells of the skin, gut and bile ducts. Reliable tests to predict GVHD are lacking. We developed an assay in which donor T cells are stimulated by patient keratinocytes (KCs), compared that with stimulation by patient peripheral blood mononuclear cells (PBMCs) and studied the relationship to GVHD. In 27 patients undergoing HLA-identical BMT for haematological malignancies, donor T-cell reactivity was determined as the helper T-lymphocyte precursor (HTLp) frequency against host PBMCs (25 patient-donor pairs) and host KCs (20 patient-donor pairs). KCs were obtained by shave biopsies and cultured with interferon (IFN)-gamma to induce HLA class II expression. In assays using patient KCs and donor T cells, anti-CD28 antibody was added to compensate for the lack of co-stimulatory molecules on KCs. Results were related to the occurrence of GVHD. As BMTs were performed with partially T cell-depleted grafts, GVHD was limited to grade 0 (five patients), grade I (seven patients) and grade II (12 patients). No differences were found in donor T-cell reactivity to patient PBMCs, as expressed as HTLp frequency in patients with or without GVHD. However, significant differences (P < 0.01) were found in donor T-cell reactivity to patient KCs when comparing patients with and without GVHD. Donor HTLp frequencies against patient KCs give a better prediction of GVHD than those against patient haemopoietic cells following HLA-identical BMT, which may indicate that at least some minor non-HLA histocompatibility antigens present on KCs are different from those on haemopoietic cells.

Bone Marrow Transplantation↗
PubMed1999

CD28 induces cell cycle progression by IL-2-independent down-regulation of p27kip1 expression in human peripheral T lymphocytes.

CD28 is the primary T cell costimulatory receptor, and upon ligation with its ligands, it enhances T cell proliferation and IL-2 synthesis. In this study we examined the role of CD28 in the initial proliferative response and cell cycle entry of T lymphocytes. Stimulation through CD3 alone resulted in a poor proliferative response, while in the presence of CD28 costimulation a strong increase in the number of cells in S-phase could be detected after 48 h of stimulation. CD28 costimulation enhanced expression of cyclin D3 and induced down-regulation of p27kip1 expression. Cross-linking CD28 was much more effective in inducing cyclin D3 expression and in down-regulating p27kip1 expression than addition of IL-2. Blocking experiments, using antibodies that neutralize IL-2 or the IL-2 receptor, showed that the effects induced by CD28 are independent of endogenous IL-2. Moreover, using a variety of immunosuppressants that interfere with IL-2 signaling pathways, we were able to show that IL-2 is not required for cell cycle entry induced by CD28 costimulation. From these experiments it can be concluded that CD28 and IL-2 use different signaling pathways for down-regulation of p27kip1 expression. We hypothesize that costimulation through CD28 is responsible for initial cell cycle entry of T lymphocytes, while IL-2, which is produced after costimulation, might be involved in sustaining proliferation.

CD28 Antigens↗
PubMed1999

Selective depletion of major and minor histocompatibility antigen reactive T cells: towards prevention of acute graft-versus-host disease.

Development of acute graft-versus-host disease (aGVHD) following HLA-identical sibling bone marrow transplantation (BMT) remains a serious complication. A selective depletion of T cells has proved to be effective in preventing aGVHD but is associated with relapse and increased incidence of infection. As aGVHD is directed mainly against epithelial tissues we examined whether it would be feasible to selectively deplete T cells reactive with epithelial cells whilst preserving other specificities. Donor T cells which express HLA-DR, CD25, CD69 and CD71 activation markers after cocultivation with patient keratinocytes were depleted using magnetic cell separation techniques. Depletion of major as well as minor histocompatibility antigen activated T cells revealed a significant (P = 0.004 and P = 0.031, respectively) 10-fold decrease in the frequency of donor T lymphocyte precursors reactive with patient keratinocytes. The frequency reactive with third-party and patient peripheral blood mononuclear cells, including leukaemia cells, remained unchanged, supporting the notion that aGVHD and graft-versus-leukaemia (GVL) may be separable. This alloantigen-specific depletion may be used in matched unrelated as well as HLA-identical sibling BMT for reducing aGVHD whilst conserving GVL.

Adult↗
PubMed1996

Human B7-1 is more efficient than B7-2 in providing co-stimulation for alloantigen-specific T cells.

Besides a signal via the T cell receptor/CD3 complex, an additional costimulatory signal is required for optimal T cell activation. This signal can be delivered by interaction of either B7-1 or B7-2 expressed by antigen-presenting cells with CD28 on the T cells. Comparison of the function of B7-1 and B7-2 in different experimental animal systems generated conflicting data on the roles for the co-stimulatory molecules. We therefore investigated whether there are differences between B7-1 and B7-2-mediated co-stimulation in an alloantigen-specific primary T cell response induced by B7-transfected human cell lines of epithelial origin. Both transfected keratinocyte cell lines efficiently induce T cell proliferation and the ratios of stimulator versus responder cells are similar. The kinetics of proliferation and interleukin (IL)-2, IL-4 and interferon-gamma production are also comparable between both transfectant lines. However, despite equal B7 expression levels, it is consistently found that the magnitude of the B7-1-induced T cell proliferation was higher than that of B7-2. Comparison of precursor frequencies of helper T lymphocytes responsive with either B7-1 or B7-2 revealed that the frequency of B7-1-responsive T cells was higher than that of B7-2, and that the frequency of cells activated by a combination of B7-1 and B7-2 did not differ significantly from that of B7-1 alone. We therefore conclude that the B7-2-responsive T cells are part of the B7-1-responsive population, and that B7-1 on keratinocytes is more efficient in providing co-stimulation for alloantigen-specific T cells.

Antigens, CD↗
PubMed1993

A peptide variant of an arthritis-related T cell epitope induces T cells that recognize this epitope as a synthetic peptide but not in its naturally processed form.

The immune system has the potential to utilize a diverse T cell repertoire for the recognition of Ag in the context of MHC molecules. Here we describe the analysis of two rat T cell clones, both of which recognize a synthetic peptide comprised of the arthritis-associated 180-188 amino acid sequence of the mycobacterial 65-kDa heatshock protein (hsp65 180-188), but which differ in the recognition of the naturally processed hsp65. The arthritogenic T cell clone A2b, generated by immunization with whole Mycobacterium tuberculosis, recognized the hsp65 180-188 synthetic peptide as well as the processed hsp65, whereas T cell clone ATL11, generated after immunization with a single amino acid substituted peptide analog of hsp65 180-188, recognized peptide hsp65 180-188 but not the processed hsp65. For both T cell clones the minimal stimulatory sequence was hsp65 180-186. However, within this minimal stimulatory sequence marked differences between the clones were found with regard to peptide residues interacting with the TCR. Furthermore, addition of extra residues at the N terminus of the hsp65 180-186 sequence abrogated the recognition by clone ATL11, but not by A2b. These findings demonstrate that, upon in vivo immunization with a synthetic peptide comprised of a single amino acid variant of a T cell epitope, T cells can be triggered that recognize a peptide comprised of the original epitope sequence, but that do not recognize this epitope in its naturally processed protein fragment. The possibility of triggering such T cells by immunization with synthetic peptides, may well have consequences for the design of peptide vaccines or peptide immunomodulatory agents.

Amino Acid Sequence↗
PubMed1981

Brain adrenocorticotrophin after adrenalectomy and sham-operation of rats.

The influence of adrenalectomy on the level of immunoreactive 18-24 ACTH extracted from hypothalamus, hippocampus and pituitary gland of rats was investigated. Brain ACTH was further characterized by fractionation by gel-permeation chromatography. Porcine 1-39 ACTH was exposed to synaptic plasma membranes in vitro in order to evaluate the role of metabolic conversion in changes of brain ACTH content. Removal of the adrenals, when compared with sham-adrenalectomy, resulted in a transient depletion of ACTH content in the anterior pituitary gland and the hippocampus, but not in the hypothalamus and the neurointermediate lobe. However, sham-adrenalectomy caused a transient reduction in levels of ACTH when compared with levels before operation in all tissues studied. The effects of adrenalectomy on hippocampal ACTH content persisted in hypophysectomized rats. Treatment of adrenalectomized rats with corticosterone failed to restore the reduced ACTH content when it was administered in doses that completely suppressed the release of pituitary ACTH. Adrenal steroids, however, may exert a direct effect on the metabolism of ACTH in the brain as judged from the in-vitro studies with porcine 1-39 ACTH exposed to a synaptosomal plasma membrane fraction of hippocampal tissue. The present study suggests that control of brain ACTH occurs independently of the control of pituitary ACTH release.

Adrenalectomy↗
PubMedDate not supplied

Involvement of ACTH and MSH in active and passive avoidance behavior.

Intracerebroventricular injection of antiserum to alpha--MSH induces a weak reduction of passive avoidance latencies after administration prior to retention testing. Administration of antiserum to ACTH 1--24 induces a more marked effect in this respect, whereas injection of a combination of these antisera results in the strongest reduction of passive avoidance retention. No effect of this treatment is observed when these antisera are injected immediately after the learning trial. In active avoidance behavior a facilitation of extinction of the response is observed after intracerebroventricular administration of the antisera prior to each extinction session. This effect is comparable with the one observed in passive avoidance behavior. From these data it is suggested that ACTH and alpha-MSH play an important role in processes related to the retrieval of information stored in the brain.

Adrenocorticotropic Hormone↗