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Biomedical subjects

P Racz

Publications and source records attributed to P Racz.

At least 55 records · Page 3Linked to original sources
PubMed1996

Splenectomy for suspected malignant lymphoma in two patients with loiasis.

Intrasplenic lesions can cause diagnostic difficulties because malignant diseases can be excluded only by histologic examination. We present the cases of two patients with splenic manifestations of loiasis. Both patients had visited central Africa. Several years later, intrasplenic lesions were found during routine examinations (for chest trauma and employment, respectively). Both patients underwent splenectomies because malignant lymphoma was suspected. In both cases, histologic examination of the spleen showed eosinophilic granulomata with multiple Loa loa microfilariae.

Adult↗
PubMed1996

Human antibodies that neutralize primary human immunodeficiency virus type 1 in vitro do not provide protection in an in vivo model.

Recently, conflicting data have been published about the ability of antibodies which efficiently neutralize T cell-adapted human immunodeficiency virus type 1 (HIV-1) strains to neutralize primary HIV-1 strains in vitro and in vivo. Here we present data indicating that such antibodies fail to neutralize primary HIV-1 strains in vivo. To this end, a newly developed chimeric human-to-mouse model was used, in which several aspects of primary HIV-1 infection are mimicked. Poly- and monoclonal antibodies protected the grafted human cells, in a dose-dependent way, from infection with T cell-adapted HIV-1 in this system. A human monoclonal antibody specific for the CD4 binding domain that efficiently neutralizes HIV-1 IIIB in vitro did not protect the human graft from HIV-1 IIIB infection. None of the antibodies provided protection in the in vivo model against infection with primary HIV-1 strains, although they were able to neutralize these same strains in vitro.

Animals↗
PubMed1996

An env gene derived from a primary human immunodeficiency virus type 1 isolate confers high in vivo replicative capacity to a chimeric simian/human immunodeficiency virus in rhesus monkeys.

To explore the roles played by specific human immunodeficiency virus type 1 (HIV-1) genes in determining the in vivo replicative capacity of AIDS viruses, we have examined the replication kinetics and virus-specific immune responses in rhesus monkeys following infection with two chimeric simian/human immunodeficiency viruses (SHIVs). These viruses were composed of simian immunodeficiency virus SIVmac239 expressing HIV-1 env and the associated auxiliary HIV-1 genes tat, vpu, and rep. Virus replication was assessed during primary infection of rhesus monkeys by measuring plasma SIVmac p27 levels and by quantifying virus replication in lymph nodes using in situ hybridization. SHIV-HXBc2, which expresses the HIV-1 env of a T-cell-tropic, laboratory-adapted strain of HIV-1 (HXBc2), replicated well in rhesus monkey peripheral blood leukocytes (PBL) in vitro but replicated only to low levels when inoculated in rhesus monkeys. In contrast, SHIV-89.6 was constructed with the HIV-1 env gene of a T-cell- and macrophage-tropic clone of a patient isolate of HIV-1 (89.6). This virus replicated to a lower level in monkey PBL in vitro but replicated to a higher degree in monkeys during primary infection. Moreover, monkeys infected with SHIV-89.6 developed an inversion in the PBL CD4/CD8 ratio coincident with the clearance of primary viremia. The differences in the in vivo consequences of infection by these two SHIVs could not be explained by differences in the immune responses elicited by these viruses, since infected animals had comparable type-specific neutralizing antibody titers, proliferative responses to recombinant HIV-1 gp120, and virus-specific cytolytic effector T-cell responses. With the demonstration that a chimeric SHIV can replicate to high levels during primary infection in rhesus monkeys, this model can now be used to define genetic determinants of HIV-1 pathogenicity.

Animals↗
PubMed1996

Differences in the germinal centres of palatine tonsils and lymph nodes.

The germinal centres of human palatine tonsils typically have four clearly recognizable compartments. The dark zone is identified by the presence of centroblasts and a thin follicular dendritic cell (FDC) network. The dense FDC network is divided into a CD23(low/-) portion adjacent to the dark zone (the basal light zone) and a CD23(high) portion, the apical light zone). The outer zone, which lies between the apical light zone and the follicular mantle, has only fine CD23- FDC processes. While these compartments were seen in 48 follicles from eight tonsils, the compartmental structure of 54 germinal centres in lymph nodes from 11 individuals was markedly different. The CD23+ FDC network in lymph node follicles extended into part of the dark zone and the inner part of the follicular mantle, and consequently no outer zone or basal light zone was identified. In both the lymph nodes and tonsils most T cells were CD4+ and located outside the dark zone; the concentration of these cells at the edge of germinal centres was typical of tonsil centres but was noted only occasionally in lymph nodes. The substantial minority of T cells that were CD4,CD57+ were located mainly in the dense FDC network.

Adolescent↗
PubMed1994

Follicular dendritic cells retain HIV-1 particles on their plasma membrane, but are not productively infected in asymptomatic patients with follicular hyperplasia.

During HIV-1 infection, extensive alterations can be observed in the germinal centers (GCs) of lymphatic tissue. The initial hyperplasia of GCs is followed by disintegration and involution of these structures. The process is accompanied by progressive destruction of the network of follicular dendritic cells (FDCs). We investigated whether or not the destruction of GCs is caused by HIV-1 infection of FDCs in vivo. FDCs were purified by FACS or magnetic cell sorter (MACS) from enlarged lymph nodes (LNs) of four asymptomatic HIV-1-infected patients with persistent generalized lymphadenopathy. In situ hybridization demonstrated positive signals for HIV-1 RNA on the cell membrane of FDCs. Virus particles attached to the dendritic network could be demonstrated by electron microscopy, but budding was not seen. Furthermore, proviral DNA was detected by nested PCR (NPCR) in limiting dilution assays of FACS-purified FDCs (up to 1.0 x 10(4) cells) in only one cell fraction. In comparison, proviral DNA could be found in 5.0 x 10(3) to 2.5 x 10(5) FACS-purified Th cells obtained from peripheral blood and in 7.5 x 10(5) to 2.5 x 10(4) Th cells from LN of the same patients. In conclusion, FDCs retain HIV-1 particles on their cell membrane during HIV-1 infection, but the progressive destruction of FDC in vivo is probably not caused by a productive infection of FDCs with HIV-1.

Cell Membrane↗
PubMed1994

Conditional ablation of dendritic cells in transgenic mice.

Dendritic cells (DC) are professional Ag-presenting cells that play a major role in T cell-mediated immune responses and in thymocyte differentiation. To better analyze their physiological importance, we sought to generate transgenic mice presenting a conditional DC deficiency. We used a strategy based on the cell-specific expression of a suicide gene. The DC-targeted expression is obtained using HIV regulatory sequences; indirect evidence has suggested that these sequences control a preferential expression in DC. The suicide gene is the herpes simplex virus type 1 thymidine kinase (HSV1-TK) which allows conditional ablation of dividing HSV1-TK-expressing cells by converting nucleoside analogs such as ganciclovir (GCV) into toxic molecules. We generated transgenic mice expressing an HSV1-TK gene transcribed from HIV regulatory sequences. A low but significant HSV1-TK expression was observed in mature DC and DC precursors grown from granulocyte-macrophage colony-stimulating factor-supplemented bone marrow cultures. These HSV1-TK-expressing DC precursors are specifically killed by GCV. We next treated transgenic mice with GCV, and obtained a specific ablation of DC in spleen and thymus. Ninety percent of spleen DC could be depleted within a week, indicating a turnover rate of approximately 15% per day. Interestingly, this DC depletion always correlated with a major thymic atrophy and disappearance of CD4+CD8+ thymocytes. This animal model should help to assess the physiological role of DC in the immune response and in thymocyte differentiation. It should also help to appreciate the consequences of DC dysfunction in pathological situations, such as HIV-infection or allograft rejection.

Animals↗
PubMed1994

Immunopathogenic events in acute infection of rhesus monkeys with simian immunodeficiency virus of macaques.

Infection of the rhesus monkey with simian immunodeficiency virus of macaques (SIVmax) was employed to explore the early immune events associated with the initial containment of an acute AIDS virus infection. In nine rhesus monkeys infected intravenously with uncloned SIVmac strain 251, high-level p27 plasma antigenemia was usually detected transiently from approximately day 7 through day 21 following virus inoculation. SIVmac replication in lymph nodes measured by in situ RNA hybridization closely paralleled the time course and magnitude of viremia. The containment of SIVmac spread by 3 to 4 weeks following infection suggests an efficient, early immune control of this virus infection. Anti-SIVmac antibodies were first detected in the blood at approximately day 14. At the time antigenemia was decreased or cleared, SIVmac neutralizing antibodies were present. A rise in circulating and lymph node CD8+ T cells also occurred coincident with the clearance of antigenemia and persisted thereafter. These CD8+ lymphocytes in lymph nodes had increased expression of both major histocompatibility complex class II and the adhesion molecule LFA-1; they also demonstrated decreased expression of the naive T-cell-associated CD45RA molecule. SIVmac-specific cytotoxic T-lymphocyte precursors were detected in both blood and lymph node by 7 days post-virus inoculation. These studies indicate that both virus-specific humoral and cellular immune mechanisms in blood and lymph node are associated with the clearance of viremia that occurs within the first month of infection of rhesus monkeys with SIVmac.

Animals↗
PubMed1993

Massive covert infection of helper T lymphocytes and macrophages by HIV during the incubation period of AIDS.

Animal and human lentiviruses elude host defences by establishing covert infections and eventually cause disease through cumulative losses of cells that die with activation of viral gene expression. We used polymerase chain reaction in situ double-label methods to determine how many CD4+ lymphocytes are latently infected by human immunodeficiency virus (HIV) in patient lymph nodes and whether the pool of infected cells is large enough to account for immune depletion through continual activation of viral gene expression and attrition of cells responding to antigens. We discovered an extraordinarily large number of latently infected CD4+ lymphocytes and macrophages throughout the lymphoid system from early to late stages of infection, and confirmed the extracellular association of HIV with follicular dendritic cells. Follicular dendritic cells may transmit infection to cells as they migrate through lymphoid follicles. Latently infected lymphocytes and macrophages constitute an intracellular reservoir large enough ultimately to contribute to much of the immune depletion in AIDS, and represent a difficult problem that must be resolved in developing effective treatments and protective vaccine.

Acquired Immunodeficiency Syndrome↗
PubMed1993

Optimizing follicular dendritic cell isolation by discontinuous gradient centrifugation and use of the magnetic cell sorter (MACS).

Follicular dendritic cells (FDC) contribute minimally to the total cell population of lymphatic tissue. In order to obtain higher numbers of viable FDC with only a small fraction of contaminating cells the following procedure was developed. Subsequent to the usual mechanical and enzymatical digestion of human tonsils, single cells were layered on top of a discontinuous bovine albumin gradient and centrifuged at 8500 x g. The suspension collected from the 1.052-1.030 interphase contained an average of 10.5% FDC. Next, the preparation was subjected to a new step involving separation of FDC previously treated with biotin-labelled KiM4 monoclonal antibody, raised against FDC, and attached via biotin-streptavidin bonding to streptavidin-conjugated paramagnetic beads. Purification on a magnetic cell sorter (MACS) yielded 3.3-10.1 x 10(6) cells with an average FDC content of 78.4%. The viability and morphology of the resulting FDC population was examined using trypan blue staining or electron microscopy. This technique will permit in vitro studies and long term cultures with FDC isolated from human lymphatic tissue.

Antibodies, Monoclonal↗
PubMed1993

Visceral leishmaniasis (kala-azar) after a visit to the Mediterranean region.

The case of a 17-year-old patient is presented who became ill 10 months after a holiday visit to Malta. Symptoms included fever peaking daily at 40 degrees C, pancytopenia, and splenomegaly. There was no evidence of bacterial or virological involvement, and probatory treatment with antibiotics followed by corticosteroids was without success. Examination of bone marrow led to the diagnosis of visceral leishmaniasis (kala-azar). A therapy with pentavalent antimony brought rapid improvement in clinical symptoms and led to complete recovery. A short review is presented of the epidemiology, diagnosis, and therapy of visceral leishmaniasis. The aim of this presentation is to remind the attendant physician of the clinical symptoms involved with the possible case of visceral leishmaniasis.

Adolescent↗
PubMed1993

Cytotoxic effector cell granules recognized by the monoclonal antibody TIA-1 are present in CD8+ lymphocytes in lymph nodes of human immunodeficiency virus-1-infected patients.

A novel monoclonal antibody (mAB) TIA-1, which recognizes a 15-kd granule-associated protein of cytotoxic T lymphocytes and natural killer cells, has been applied to sections of lymph nodes with human immunodeficiency virus (HIV)-induced lymphadenopathy (follicular hyperplasia and lymphocyte depletion). The protein recognized by this mAB induces apoptosis in permeabilized lymphocytes in vitro. While this mAB reacted with approximately 46% of paracortical CD8+ cells in control nodes, it reacted with 75% of such cells in HIV-induced follicular hyperplasia. Germinal centers of the control nodes contained few TIA-1 + cells; in follicular hyperplasia caused by HIV-1, almost all germinal center CD8+ cells were TIA-1 +. Both in the control nodes and in HIV-induced follicular hyperplasia the majority of TIA-1 + cells coexpressed CD45R0. A marked loss of CD8+TIA-1+ cells was seen in lymphocyte-depleted nodes of patients with AIDS. The loss of these cytotoxic T lymphocytes may have a significant impact on the progression of the disease.

Acquired Immunodeficiency Syndrome↗
PubMed1992

[Clinical diagnosis and neuropathologic examination findings in 20 AIDS patients].

Disorders of the central nervous system (CNS) associated with HIV infections are becoming increasingly important in the area of clinical diagnosis and treatment of patients with AIDS. The aim of this retrospective analysis of 20 patients with AIDS who died in 1989 was to compare clinical diagnosis, neuroradiological findings and treatment with the results of neuropathological studies. The neuropathological examinations revealed primary CNS lymphoma (high-grade non-Hodgkin's lymphoma) in seven cases, cerebral toxoplasmosis in four cases, haemorrhagic infarction in three cases, cerebral cryptococcosis in three cases, and one case each of infiltration of the dura by a peripheral Burkitt's lymphoma, cytomegalovirus encephalitis and bacterial meningitis. A remarkably high percentage of CNS lymphomas with no distinct clinical or neuroradiological differentiation criteria were found in this study. On the basis of these data, we conclude that stereotactic biopsy and histological diagnosis should be recommended for patients with focal intracerebral lesions who fail to respond to suitable anti-parasitic treatment.

AIDS Dementia Complex↗