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Biomedical subjects

P F Halloran

Publications and source records attributed to P F Halloran.

At least 19 recordsLinked to original sources
PubMed1992

Local T cell responses induce widespread MHC expression. Evidence that IFN-gamma induces its own expression in remote sites.

Local inflammation induces increased expression of MHC and other genes in the affected tissue because of the paracrine effects of cytokines such as IFN-gamma. We previously reported that one such process--local allograft rejection--was accompanied by increased expression of MHC in a remote tissue, namely kidney. To explore how local inflammation affects gene expression in remote tissues, we studied MHC, beta 2-microglobulin, and IFN-gamma expression in mice undergoing either of two T cell-dependent localized inflammatory processes: rejection of an ascites tumor allograft, and skin sensitization by oxazalone. As assessed by binding of radiolabeled mAb and by immunohistology, each stimulus increased MHC expression in many remote tissues, including liver, heart, pancreas, and kidney. This was associated with increases in steady state mRNA for class I, class II, and beta 2-microglobulin. MHC induction was inhibited by the in vivo administration of cyclosporine or anti-IFN-gamma mAb and did not occur in nude mice, confirming the key role of IFN-gamma released from T cells. When we examined tissues of mice with these localized inflammatory lesions for IFN-gamma mRNA levels by polymerase chain reaction, we found that IFN-gamma steady state mRNA levels were increased in the spleen and, more surprisingly, in the kidney, and in uninvolved skin. Moreover, anti-IFN-gamma inhibited the induction of IFN-gamma mRNA in the kidney, suggesting that IFN-gamma expression was induced by IFN-gamma in an autoregulatory fashion. Thus the systemic MHC induction accompanying local T cell-mediated inflammation reflects the release of IFN-gamma from the site of inflammation, but may be amplified by the ability of IFN-gamma to induce its own expression in remote tissues. This self-amplification of IFN-gamma may contribute to the ability of local inflammation to induce extensive systemic effects.

Animals↗
PubMed1992

Thymus-independent expression of a truncated T cell receptor-alpha mRNA in murine kidney.

During studies on gene expression in the kidney, we unexpectedly observed that murine kidney expresses a truncated form of TCR-alpha mRNA (1.3-1.4 kb). This transcript was not associated with the presence of complete TCR-alpha mRNA (1.7 kb) or detectable TCR-beta or -delta transcripts, thus indicating that the truncated TCR-alpha mRNA could not be attributed to blood contamination of the kidney RNA preparation. The truncated TCR-alpha message appeared to contain at least the C alpha region, as suggested by hybridization with an intra-C alpha 24 oligonucleotide probe, by amplification of the C alpha region with the polymerase chain reaction from total kidney mRNA, and by sequencing of, and hybridization with, the amplified products. In situ hybridization of kidney sections indicated that the transcript was expressed in interstitial cells. Northern blots of cortex and medulla RNA showed that the cells expressing the truncated TCR-alpha mRNA were predominantly located in the medulla. To investigate the possibility that the transcript was not produced by T cells or NK cells, fractionation of renal cell suspensions were performed. The truncated TCR-alpha mRNA was detected in a fraction containing large (low buoyant density) cells in which no expression of CD3, Thy 1, or NK-1.1 was detected, indicating that these cells are not mature T cells, do not express a functional TCR, and are not NK cells. The cells expressing the truncated TCR-alpha mRNA were radiosensitive, and were not thymus dependent, because this transcript was as abundant in nude mice as in normal mice. The transcript was not detected in bone marrow. Expression of the truncated TCR-alpha mRNA was not dependent on an intact recombinase activity as its expression was not affected by the severe combined immunodeficiency mutation. Our results show that murine kidney contains a population of radiosensitive thymus-independent large interstitial cells that express a truncated TCR-alpha mRNA that is not associated with surface expression of functional TCR. These cells may have attempted to rearrange TCR-alpha genes, suggesting that they may be related to the lymphoid lineage.

Animals↗
PubMed1992

HLA-DR expression by platelets in acute idiopathic thrombocytopenic purpura.

Induction of expression of MHC class II antigens on the surface of cells that do not ordinarily express these proteins has been implicated in the pathogenesis of autoimmunity in diabetes mellitus and autoimmune thyroiditis. Platelets express class I but not class II HLA antigens. In this report, we describe a child with acute idiopathic thrombocytopenic purpura who at the time of the thrombocytopenic episode had class II (HLA-DR) antigens on his platelets. Following recovery, the HLA-DR antigens were no longer present on the platelets. We postulated that class II had been induced on his megakaryocytes by a cytokine such as interferon gamma, and that the induced expression of class II antigens contributed to the autoimmune disorder. To substantiate this possibility we next studied class I and II antigen expression on an erythroleukaemia cell line (HEL), which has many megakaryocytic features. Following treatment of HEL cells with interferon gamma, class I expression was increased and HLA-DR antigens were induced. These observations suggest that cytokine-mediated induced HLA-DR expression may contribute to the pathogenesis of a subset of thrombocytopenias.

Blood Platelets↗
PubMed1992

Complement-dependent cytotoxicity for negative selection at the mRNA level.

Complement-Dependent Cytotoxicity (CDC) is a common technique used for isolating and characterizing cell populations. However, the molecular events resulting from CDC-mediated cell injury remain obscure. In order to use CDC as a selection procedure for studies at the RNA level, we examined if CDC is associated with rapid degradation of RNAs from target cells without affecting the stability and viability of RNAs of non-target cells. Using a model of anti-CD3-mediated CDC, we show that T cell-specific RNAs were absent immediately after CDC. However, ribosomal RNAs and mRNAs from non-targeted cells (non-T cells) were not affected by CDC. Our results indicate that CDC is associated with rapid degradation of only target cell RNAs, validating CDC as a method for cell isolation without interfering with further studies at the RNA level.

Antibodies, Monoclonal↗
PubMed1992

The significance of the anti-class I response. II. Clinical and pathologic features of renal transplants with anti-class I-like antibody.

Although the ability of preformed anti-class I antibodies to mediate hyperacute rejection is well established, their pathogenic role in acute rejection remains ill-defined. We set out to identify patients with anti-class I against donor cells and to define the clinical and pathological features of such patients. We collected sera pretransplant and in the first 3 months posttransplant from 64 renal transplant recipients (59 cadaver donors and 5 one-haplotype matched living-related donors). We assayed the sera for class I-like antibody against donor T cells in complement-dependent microcytotoxicity, with crossmatches against autologous T cells to exclude auto-antibodies. All pretransplant sera were negative against donor T cells. Of the 797 sera tested posttransplant, 131/195 sera from 13 patients were positive, and 602 sera from 51 patients were negative. All patients who formed anti-class I underwent rejections compared with only 41% of patients with no anti-class I detected (P less than 0.0005). More rejections in patients with anti-class I were classed as severe (12/15 [80%] compared with 9/28 [32%] P less than 0.005), and graft loss was significantly higher (5/13 vs. 2/51; P less than 0.002). Rejections associated with anti-class I occurred earlier; more frequently developed oliguria (35% versus 10%) and required dialysis (40% versus 10%) and biopsies (10/13 vs. 6/28); and had a higher rate of rise in serum creatinine (249 versus 79 microns/L in the first 48 hr). Biopsies during anti-class I positive rejections more frequently displayed endothelial injury in the microcirculation, neutrophils in the glomeruli and/or peritubular capillaries, and fibrin deposition in glomeruli or blood vessels. The biopsies in anti-class I negative rejection episodes tended to have tubulitis, interstitial infiltration, and blasts, suggesting that these lesions reflect T-cell-mediated mechanisms. We conclude that patients with antibody against donor class I had more severe rejection, probably because anti-class I injuries the endothelium of small blood vessels of the graft, leading to rapid functional deterioration. We believe that anti-class I may be a major factor in some severe rejection episodes.

Adolescent↗
PubMed1991

The mechanism of action of cyclosporine: a perspective for the 90's.

The introduction of cyclosporine (CyA) as a pharmacological agent has resulted not only in a dramatic improvement in the clinical management of transplant recipients but also in a better understanding of the molecular basis of the immune response, especially T cell function. Knowledge of the mechanism of action of CyA has led to exciting areas of study. Among these are the sequence of regulatory events leading to T cell activation, the potential relevance of isomerases in signal transduction pathways (as the receptor for CyA, cyclophilin has been shown to be an isomerase), the blocking effect of CyA on the development of multidrug resistance, and the striking parallelism between CyA and the newer immunosuppressive agent FK-506. These fields promise to be relevant in solving some of the crucial questions in transplantation immunology, and developing better strategies for immunosuppression.

Amino Acid Isomerases↗
PubMed1991

Interferon gamma-mediated renal MHC expression in mercuric chloride-induced glomerulonephritis.

In rodents, mercuric chloride (HgCl2) causes an autoimmune disorder with glomerulonephritis (GN), and represents an animal model for the pathogenesis of GN. We have tested the hypothesis that HgCl2 induces major histocompatibility complex (MHC) expression in renal parenchymal cells, and studied the kinetics of this induction and its temporal relation to the development of immune complex deposition in the glomeruli. Mice treated with doses of HgCl2 between 2 and 3.2 mg/kg three times for one week had increased renal expression of MHC class I and class II (at the mRNA and the product levels). Class I induction was observed in proximal tubule cells, endothelial cells and glomerular cells. Class II induction was seen mainly in interstitial cells and, to a lesser extent, in tubule cells. Renal MHC expression was maximal at one week, decreased progressively after the second week of HgCl2 administration, and reached basal levels by 23 weeks. In contrast, the amount of lymphocyte infiltration in the kidney increased from the first to the fifth week and was followed by the appearance of glomerular immune deposits from the third week on. Glomerular immune complex deposits were maximal at five weeks and, by 23 weeks, immune deposits in HgCl2-treated mice were only slightly increased over those observed in the sham group. Renal MHC induction by HgCl2 was significantly reduced by treatment with monoclonal antibody against interferon gamma.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Major histocompatibility complex antigens and murine islet allograft survival.

Immunomodulation of rodent islets can significantly prolong allograft survival. We utilized a murine model of primary islet transplantation to study the relationship between allograft survival and the quantitative pretransplant expression of class I and II MHC antigens in freshly isolated CBA/J islets, and islets subjected to 37 degrees C tissue culture, brief culture at 7 degrees C, or exposure of the donor to lipopolysaccharide. Seven-day culture resulted in decreased class II expression, a tendency to decreased class I expression, and a significant prolongation of allograft survival. Brief culture at 7 degrees C resulted in increased class I expression, a trend to decreased class II expression, and no significant change in allograft survival. Donor pretreatment with LPS resulted in increased class I expression without significant change in class II expression and was correlated with prolongation of allograft survival. These studies demonstrate that an upregulation of MHC class I by in vitro or in vivo islet pretreatment is not associated with an acceleration of islet rejection. Reduction of class II was associated with delayed rejection. These results do not support a major role of the indirect pathway of antigen presentation in islet rejection in vivo. Certain protocols that alter the usual expression of class I and II on pancreatic islets are associated with alteration in the initiation and/or propagation of the normal cell-mediated rejection process, suggesting that the concept of pretransplant treatment should continue to be pursued.

Animals↗
PubMed1990

The regulation of expression of MHC products in mice. Factors determining the level of expression in kidneys of normal mice.

Cytokines, especially IFN, have been shown to increase MHC expression above basal levels in many immunologic processes, but their contribution to normal MHC expression is unknown. Environmental stimuli, such as bacterial LPS, may provoke the secretion of cytokines which could influence MHC expression in the normal host. We therefore studied the factors influencing the normal expression of MHC products in mice, by using kidney as a representative nonlymphoid tissue. Considerable variation in MHC expression was observed between otherwise normal individuals by using indirect immunoperoxidase staining and a radiolabeled antibody binding assay. An intact T cell compartment was not necessary for normal levels of expression; in athymic nude mice and mice with severe combined immunodeficiency disease, MHC expression was similar to or greater than that of controls. Neither a course of broad spectrum antibiotics nor genetically determined resistance to LPS influenced the level of normal expression. Mice raised under germ-free conditions, on a chemically defined diet also had similar levels of MHC expression when compared with mice maintained under conventional conditions. However, when germfree mice were placed in a conventional colony, induction of both class I and II MHC products occurred. Thus, although exposure to bacterial flora or other sources of endotoxin was not required for normal MHC expression, a change in flora can up-regulate expression, probably by inducing the secretion of cytokines from non-T cells. Treatment with cyclosporine or anti-IFN antibodies produced, at most, a small reduction in the level of renal MHC expression. Therefore in some mice, a small component of MHC expression may reflect the secretion of cytokines in response to stimuli such as bacterial LPS. However, most MHC expression in nonlymphoid tissues is constitutive and independent of a physiologic IFN response.

Animals↗
PubMed1990

Progressive renal failure due to renal invasion and parenchymal destruction by adult T-cell lymphoma.

A 43-year-old patient of occult adult T-cell lymphoma (ATL) presenting with systemic illness and progressive renal failure due to lymphomatous infiltration of kidneys is described. The striking feature observed was destructive infiltration of the kidneys, by malignant CD4 cells, virtually replacing the normal renal architecture. The diagnosis of lymphoma was made by renal biopsy. Clinical features typical of ATL were hypercalcemia, lytic bone lesions, and profound wasting and inanition. The patient died rapidly despite attempted therapy. The case illustrates the potential of ATL for direct renal parenchymal destruction.

Adult↗
PubMed1990

The significance of the anti-class I antibody response. I. Clinical and pathologic features of anti-class I-mediated rejection.

In renal transplantation, preformed cytotoxic antibody against donor HLA class I antigens causes hyperacute rejection of renal allografts, but its pathogenic significance when it develops in the posttransplant period is unknown. In the present studies we describe the clinical and pathologic features of patients with rejection associated with anti-class I. In the course of 400 consecutive cadaveric renal transplants, 7 patients were identified who had antibody against donor class I HLA antigens in association with atypical but distinctive patterns of rejection. All 7 were presensitized. In 3 patients, the transplant had been inadvertently performed with a positive donor-specific T cell crossmatch. In the remaining 4, the T cell crossmatch on current sera was negative but became positive posttransplant. The clinical picture was deterioration of graft function with rapid onset of oliguria, apparently due to acute tubular necrosis, but with persistence of blood flow demonstrable by radioisotope scan studies. Renal histology showed that the typical lesions observed in cell-mediated rejection, such as tubulitis and interstitial infiltration, were absent. Granular complement deposition (6), polymorphonuclear infiltration (6), and endothelial injury in the microvasculature (6) were common, and mononuclear infiltrates were absent (2) or not prominent (4). In 3 patients the glomerular changes resembled a picture of hemolytic uremic syndrome, with capillary fibrin thrombi and widening of the subendothelial space. IgG staining was negative. The pathologic features suggest that anti-class I antibody appearing or persisting in the early posttransplant period injures the endothelium of the microvasculature, with the clinical presentation different from that of hyperacute rejection. Particularly in sensitized patients, rapid deterioration in function, leading to a picture of acute tubular necrosis, with pathologic features of endothelial injury in the microcirculation, should suggest the diagnosis of anti-class I-mediated rejection.

Adult↗