RESUMO
BACKGROUND: Non-Hodgkin lymphoma is a systemic disease and various organs can therefore be affected. Ocular manifestations of non-Hodgkin lymphomas are possible but involvement of the eyelids or lacrimal glands are uncommon. CASE REPORT: A 63-year-old female patient suffered from a painless upper eyelid swelling of the left eye for 3 weeks. The anterior and posterior parts of the eyes showed no pathologic signs and X-ray examination of both orbits revealed no pathologic findings. Magnetic resonance imaging and computer tomography of the head revealed a neoplasm of the left lacrimal gland and also of the left parotid gland. The histologic examination revealed a recurrent non-Hodgkin lymphoma. CONCLUSIONS: The causes of eyelid swellings can be multiple, however, painless swellings may also be caused by neoplasms. In the case described here it was interesting that behind a painless eyelid swelling even a systemic disorder was hidden, i.e. a recurrence of a non-Hodgkin lymphoma, which was localized in the lacrimal gland.
Assuntos
Neoplasias Oculares , Aparelho Lacrimal , Linfoma Folicular , Adulto , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Murinos , Diagnóstico Diferencial , Edema/etiologia , Neoplasias Oculares/diagnóstico , Neoplasias Oculares/diagnóstico por imagem , Neoplasias Oculares/tratamento farmacológico , Neoplasias Oculares/cirurgia , Neoplasias Oculares/terapia , Doenças Palpebrais/etiologia , Feminino , Humanos , Imunoterapia , Aparelho Lacrimal/diagnóstico por imagem , Aparelho Lacrimal/patologia , Metástase Linfática/patologia , Linfoma Folicular/diagnóstico , Linfoma Folicular/diagnóstico por imagem , Linfoma Folicular/tratamento farmacológico , Linfoma Folicular/patologia , Linfoma Folicular/cirurgia , Linfoma Folicular/terapia , Imageamento por Ressonância Magnética , Rituximab , Tomografia Computadorizada por Raios XRESUMO
Transplantation of unmatched allogeneic corneas into highly vascularized recipient eyes under the cover of short-term immunosuppression with cyclosporine enables permanent engraftment. The aim of this study was to further elucidate the mechanism(s) underlying this tolerant state. In eight "high-risk" cornea recipients the clone sizes of donor-specific and third-party reactive cytotoxic T cell precursors were assessed by limiting dilution analyses before and at three and six months after transplantation. Acquired allograft tolerance in these patients was not accompanied by clonal reduction of donor-specific CTL-p, whereas in the case of an irreversible rejection the donor-specific CTL pool size was significantly enlarged. This donor-specific CTL-p increase could already be seen two months before clinical manifestation. These patterns differed from that of tolerant renal transplant patients, in whom marked and donor-specific reduction of CTL-p was observed. During rejection identical patterns with increasing donor-specific CTL-p frequencies were seen in both groups of patients. We conclude that induction of tolerance by short-term CsA to unmatched cornea grafts is not caused by clonal reduction of the effector precursor cell pool.
Assuntos
Transplante de Córnea , Ciclosporinas/farmacologia , Tolerância Imunológica , Linfócitos T Citotóxicos/imunologia , Adulto , Idoso , Fatores Biológicos/biossíntese , Citocinas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Risco , Transplante HomólogoRESUMO
We have recently developed a sensitive limiting dilution (LD) culture system to measure human alloreactive cytotoxic T lymphocyte precursors (CTL-p) in a given lymphoid cell population. We have now used this system to determine frequencies of donor HLA antigen-inducible CTL-p in the peripheral blood of human allograft recipients at various stages after transplantation. All patients (1 pancreas recipient and 9 kidney recipients) were on continuous cyclosporine treatment throughout the study. We report that, in patients with a well-functioning kidney graft (6/9), the number of donor-reactive CTL-p among peripheral blood lymphocytes decreased within 3-8 months after transplantation--in some cases (2/6) more than 10-fold. In contrast, frequencies of CTL-p with specificity for third-part HLA antigens remained largely unaltered in these patients. Furthermore, no decrease of donor-reactive CTL-p frequencies was seen in 3 of 4 patients showing clinical symptoms of graft rejection. These results indicate that functional clonal deletion of antigraft-reactive CTL-p may contribute to the state of graft tolerance in certain patients with a well-functioning kidney allograft.
Assuntos
Células-Tronco Hematopoéticas/citologia , Transplante de Rim , Linfócitos T Citotóxicos/imunologia , Células Cultivadas , Ciclosporinas/administração & dosagem , Sobrevivência de Enxerto , Antígenos HLA/imunologia , Humanos , Rim/fisiologia , Contagem de Leucócitos , Transplante de Pâncreas , Prednisona/administração & dosagem , Transplante HomólogoRESUMO
Autologous cultured epidermis (CE) grown from small skin biopsies in vitro has been successfully applied for wound grafting in humans. Since it has been reported recently that allogeneic CE might be tolerated as permanent wound cover, we investigated the properties of CE and its use as autologous and allogeneic grafts. Except for some differences, such as the absence of Langerhans cells and the lack of a stratum corneum, CE resembled its natural analogue. Autologous CE applied for grafting of leg ulcers and various surgical skin defects adhered firmly and permanently to the wound bed within 2 weeks, became regularly stratified, and formed a stratum corneum. Langerhans cells gradually entered the grafts; the dermis contained no inflammatory infiltrate. Allogeneic CE unmatched for MHC and blood group antigens used to partially cover tangentially excised third-degree burns, donor sites of split-thickness skin, and a defect after tumor excision initially survived well like the autografts. However, they were completely rejected after 10-22 (mean, 14.5) days, which is 4-5 days later than reported for split-thickness skin allografts. Clinically, rejection presented as "melting" of the graft. (Immuno)histologically, we found a dense mononuclear dermal infiltrate consisting predominantly of activated T cells, vacuolization, and single-cell necrosis of keratinocytes, as well as HLA-DR expression on keratinocytes, and finally separation and lysis of the epidermis. Limiting dilution analysis in 2 out of 4 allograft recipients revealed a considerable increase of circulating donor-specific cytotoxic T cell precursors during graft rejection. We conclude that grafting of allogeneic CE does not lead to permanent but to slightly prolonged graft survival.
Assuntos
Epiderme/transplante , Rejeição de Enxerto , Sobrevivência de Enxerto , Células de Langerhans , Cicatrização , Adolescente , Adulto , Células Cultivadas , Epiderme/análise , Epiderme/ultraestrutura , Feminino , Humanos , Isoantígenos/análise , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Linfócitos T Citotóxicos , Transplante Autólogo , Transplante HomólogoRESUMO
In 5 recipients of cadaveric renal allografts, we tested the influence of prophylactic immunosuppression with cyclosporine (Cy A) and low dose prednisone on in vitro proliferative T cell responses, T-helper/T-suppressor cell ratios and spontaneous- or lectin-induced unspecific suppressor cell activity and on serum mediated inhibition of proliferative T cell responses. Results revealed a reduction of the overall proliferative T cell responsiveness, which was particularly seen in cultures supplemented with autologous serum and was maximally expressed after approximately 30 days of treatment. This impaired proliferative capacity was neither accompanied by shifts of the T-helper/T-suppressor ratios nor by alterations of spontaneous- or lectin-induced suppressor activity. The capacity of patients' plasma to inhibit lymphocyte proliferation was also tested. Results indicated that almost every plasma of Cy A patients was capable of inhibiting mixed lymphocyte culture (MLC) responses. The inhibitory capacities of these plasma, however, were not directly correlated with their Cy A content.
Assuntos
Ciclosporinas/uso terapêutico , Transplante de Rim , Ativação Linfocitária/efeitos dos fármacos , Prednisona/uso terapêutico , Adulto , Humanos , Terapia de Imunossupressão , Técnicas In Vitro , Masculino , Pessoa de Meia-Idade , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T Reguladores/imunologiaRESUMO
Alloantigen-specific cytotoxic T lymphocyte precursor (CTL-p) frequencies were analyzed in ten patients with histologically proven breast cancer receiving prophylactic RT. The frequency of CTL-p was assessed by limiting dilution (LD) analyses before, immediately after discontinuation of treatment and at various times following RT. The number of pbmnc, adherent cells and T cells was determined in parallel. Local RT led to a minor and transient reduction of CTL-p frequencies lasting approximately three months: on average a 25% decrease of CTL-p numbers was seen immediately after RT. Three months following treatment, a 20% reduction was still evident. Values subsequently returned to pretreatment levels. Moreover, these changes in the frequency of antigen-specific CTL were accompanied by a 25% to 39% decrease in the blood T cell counts lasting for more than 12 months. The reductions following local RT were less pronounced than those induced by immunosuppressive drugs in allograft recipients.
Assuntos
Neoplasias da Mama/radioterapia , Síndromes de Imunodeficiência/etiologia , Teleterapia por Radioisótopo/efeitos adversos , Radioterapia de Alta Energia/efeitos adversos , Linfócitos T Citotóxicos/efeitos da radiação , Adulto , Idoso , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/imunologia , Neoplasias da Mama/cirurgia , Terapia Combinada , Feminino , Humanos , Leucopenia/etiologia , Pessoa de Meia-Idade , Linfócitos T Citotóxicos/imunologia , Tamoxifeno/uso terapêuticoRESUMO
Proliferative and cytolytic lymphocyte responses and the influence of exogenous interleukin 2 (IL2) on cell-mediated lympholysis (CML) reactivity were evaluated in 12 allograft recipients. Responses were induced by mitogenic lectins or by donor and third-party cells. Patients were tested immediately before transplantation (Tx) and one and three months after grafting. Prophylactic immunosuppression consisted of Cyclosporin A (CyA) and low-dose prednisone (P). Analysis of post transplant cells revealed a reduced overall proliferative T cell responsiveness induced by both alloantigens and mitogenic lectins. No evidence for donor-specific reduction of MLC responses was seen. Overall CML reactivity of post-Tx lymphocytes was also impaired. This was accompanied by donor-specific CML non-reactivity in six of seven patients with quiescent grafts. In these patients, the cytolytic potential against donor cells could be restored when maximal T cell help via exogenous IL2 was provided.
Assuntos
Interleucina-2/farmacologia , Linfócitos T Citotóxicos/efeitos dos fármacos , Adulto , Ciclosporinas/imunologia , Feminino , Humanos , Imunossupressores , Interleucina-2/administração & dosagem , Masculino , Pessoa de Meia-Idade , Prednisona/imunologia , Linfócitos T Citotóxicos/análiseRESUMO
AIMS: To define the effect of the neuropeptides substance P, calcitonin gene related peptide, vasoactive intestinal polypeptide, neuropeptide Y, and secretoneurin on the proliferation of human retinal pigment epithelial (RPE) cells. METHODS: ARPE-19 cells were used. The cells were cultured in Dulbecco's modified Eagle's medium. 1000 and 2000 cells were incubated with the peptides for 3 and 5 days, and the effect of the peptides was evaluated by an ATP lite assay dose dependently. Furthermore, specific antagonists at 10(-6) M were used to find out whether the effect would be reversed. RESULTS: In brief, each of the peptides tested had an inhibiting effect. This inhibiting effect was weak but highly significant, averaging 10% to 15%, and was most pronouncedly seen at concentrations between 10(-10) M and 10(-14) M. Each antagonist reversed the inhibiting effect fully. CONCLUSIONS: These results clearly indicate that RPE cells are under neural control and the low effective concentration of the peptides may be the one physiologically acting on these cells. The results are of important relevance both physiologically and pathophysiologically: physiologically, the inhibitory effect may mean that these peptides cause the cells to remain in a differentiated condition. Pathophysiologically, the findings are relevant in proliferative vitreoretinopathy where RPE cells proliferate in excess. The authors hypothesise that the inhibiting effect diminishes when these cells are swept out and actively migrate from their physiological location and thus, dedifferentiate and begin to proliferate. This hypothesis improves the knowledge of the initial processes in the pathogenesis of the disease as there seems to be a discrepancy between facilitatory and inhibitory influences favouring the former in proliferative vitreoretinopathy. Furthermore, these neuropeptides constitute the first endogenous inhibitors of RPE cell proliferation.
Assuntos
Neuropeptídeos/farmacologia , Epitélio Pigmentado Ocular/efeitos dos fármacos , Peptídeo Relacionado com Gene de Calcitonina/farmacologia , Divisão Celular/efeitos dos fármacos , Linhagem Celular , Depressão Química , Relação Dose-Resposta a Droga , Humanos , Neuropeptídeo Y/farmacologia , Epitélio Pigmentado Ocular/citologia , Secretogranina II , Substância P/farmacologia , Fatores de Tempo , Peptídeo Intestinal Vasoativo/farmacologiaAssuntos
Tolerância Imunológica , Transplante de Rim/imunologia , Transplante Homólogo/imunologia , Transplante de Medula Óssea/imunologia , Transplante de Córnea/imunologia , Ciclosporinas/uso terapêutico , Epiderme/transplante , Humanos , Transplante de Pele/imunologia , Linfócitos T Citotóxicos/imunologiaRESUMO
Stimulation of T lymphocytes with alloantigen leads to release of both IL-2 and IFN-gamma. IL-2 enhances clonal expansion of alloantigen-activated T cells. This permits it to overcome acquired allograft tolerance which, at the efferent limb of the cellular immune response, is caused by reduced clone size of donor-specific cytotoxic lymphocyte precursor cells. Cells exhibiting a low constitutive expression of class I MHC antigenes are refractory to lysis by cytotoxic T cells. This second type of tolerance located at the level of the allogeneic target cells can be easily broken by exogenous IFN-gamma, which increases the density of class I MHC antigens. There is suggestive evidence for enhanced endogenous production of lymphokines during rejection of cardiac allografts in mice and men. Rejection episodes are also associated with increased expression of class I and elevated frequency of class II MHC antigen-positive cells in the cardiac transplants. Whereas early immune recognition of histoincompatible grafts is primarily related to the presence of genetic barriers between donor and recipient, the further amplification of alloreactivity is driven by the release of antigen-unspecific lymphokines. Production of endogenous lymphokines can be modified by a variety of means: methylprednisone, ciclosporin and specific antibodies against lymphokines or their receptors represent effective inhibitors of this amplification mechanism which can finally lead to irreversible graft damage. It is well established in clinical experience that infectious complications subsequent to allografting may precipitate rejection or graft-vs.-host disease. Our finding of increased endogenous IFN-gamma levels during infections, in particular in those caused by cytomegalovirus, provides an explanation for this association.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Rejeição de Enxerto/efeitos dos fármacos , Transplante de Coração , Interferon gama/farmacologia , Interleucina-2/farmacologia , Humanos , Ativação Linfocitária , Complexo Principal de Histocompatibilidade , Linfócitos T Citotóxicos/imunologiaRESUMO
To better understand the phenomenon of P-glycoprotein (P-170) expression we investigated lymphocyte subpopulations for P-170 function in healthy volunteers. Studies were based on three-colour flow cytometry including the fluorescent probe rhodamine 123 (Rh123), which is transported by P-170. Marked Rh123 efflux was detected in CD8+ T lymphocytes with CD8+/CD45RA+ T cells (naive cells) showing significantly higher P-170 activity as compared with CD8+/CD45RA- cells (P<0.04). Vice versa, CD8+/CD45RO+ T cells (memory cells) demonstrated less P-170 activity than CD8+/CD45RO- cells (P<0.04). P-170 function was less prominent in CD4+ T cells, however, Rh123 efflux was higher in the CD4+/CD45RA+ and CD4+/CD45RO- subpopulations (P<0.025) corresponding to the CD8+ results. Dye efflux differed significantly between activated and non-activated CD8+ and CD4+ as well as CD8+/CD11b+ and CD8+/CD11b- T lymphocytes. Since CD16+ natural killer cells (NK) expressed the highest level of P-170, the NK cytotoxicity against 51Cr-labelled K562 target cells was assayed in the presence or absence of P-170 inhibitors. NK related cytotoxicity was significantly reduced in the presence of R-verapamil and dexnigaldipine-HCP in a dose-dependent manner. The differential expression of P-170 activity in naive and memory T cells together with the reduced NK related cytotoxicity in the presence of MDR-modulators suggest a physiological role of P-170 in immunological functions of these lymphocyte subsets. Consequently, the addition of MDR modulators to conventional chemotherapy as a strategy to overcome drug resistance should consider possible adverse immunosuppressive effects.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Citometria de Fluxo/métodos , Corantes Fluorescentes , Rodaminas , Subpopulações de Linfócitos T/metabolismo , Anticorpos Monoclonais/metabolismo , Antígenos CD/metabolismo , Resistência a Múltiplos Medicamentos , Humanos , Células Matadoras Naturais/metabolismo , Rodamina 123RESUMO
Periportal fibroplasia is the dominating feature of hepatosplenic schistosomiasis. Since monokines play an important role in the regulation of fibroplasia, tumour necrosis factor (TNF) and interleukin 1 beta (IL-1 beta) were assessed in sera and cell culture supernatants from patients with intestinal and hepatosplenic schistosomiasis before and 3-6 months after treatment with praziquantel. Uninfected controls were from the study area in Alagoas, Brazil. TNF was measured using an L-M mouse fibroblast bioassay and radioimmunoassays specific for TNF-alpha. Whereas TNF-alpha was elevated threefold in the patients' sera, three- to five-fold reductions of TNF were observed by radioimmunoassay and bioassay, respectively, in cell culture supernatants of hepatosplenic schistosomiasis patients. Significant deviations, in opposite directions, from TNF levels in control sera and supernatants are most plausible in the event of a sequestration of TNF-alpha-producing cells from the circulation. This process may be disease stage-specific since a dichotomy between incipient and advanced cases of hepatosplenic schistosomiasis became apparent in the amplitude and kinetics of changes during the follow-up after treatment.
Assuntos
Leucócitos Mononucleares/metabolismo , Hepatopatias Parasitárias/imunologia , Esquistossomose mansoni/imunologia , Esplenopatias/parasitologia , Fator de Necrose Tumoral alfa/metabolismo , Adolescente , Adulto , Idoso , Biopterinas/análogos & derivados , Biopterinas/sangue , Células Cultivadas , Criança , Feminino , Humanos , Interleucina-1/sangue , Leucócitos Mononucleares/imunologia , Hepatopatias Parasitárias/sangue , Hepatopatias Parasitárias/tratamento farmacológico , Ativação Linfocitária/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Neopterina , Praziquantel/uso terapêutico , Radioimunoensaio , Esquistossomose mansoni/sangue , Esquistossomose mansoni/tratamento farmacológico , Esplenopatias/sangue , Esplenopatias/tratamento farmacológico , Esplenopatias/imunologiaRESUMO
BACKGROUND: Subacute viral infection is known to change the phenotype of infected cells, thereby causing immune-mediated tissue damage. The aim of this study was to investigate the expression of different cell surface molecules on human retinal pigment epithelial cells (RPEC) following viral infection, with special emphasis on those having immune-regulatory functions. METHODS: Cultured RPEC were infected with cytomegalovirus (CMV), coxsackie-virus B3 (CVB) or herpes simplex virus type I (HSV). Double-staining fluorescence technique was used for visualization of virus infection and cell surface markers in the same cells by laser microscopy. RESULTS: CMV downregulated MHC class I antigens on RPEC, whereas CVB and HSV did not alter MHC class I antigen expression. No induction of class II antigens was observed in RPEC infected with CVB, HSV or CMV. The intercellular adhesion molecule ICAM-1 (CD54) was strongly expressed in uninfected RPEC, and a slight increase was observed after virus infection. Vascular cell adhesion molecule 1 (VCAM-1) was expressed in low amounts in both uninfected and infected RPEC. No expression of intercellular adhesion molecule 2 (ICAM-2), E-selectin ELAM-1 or lymphocyte-function-associated antigen 1 (LFA-1) was observed on RPEC before or after virus infection. CONCLUSION: Downmodulation of immune-regulating cell surface antigens has been suggested to provide a means of long-term survival of viruses in the infected cell, favoring establishment of persistent infection. Our observation in cultured human RPEC indicates that this mechanism might indeed contribute to the development of disease affecting retinal tissue.
Assuntos
Antígenos de Superfície/metabolismo , Moléculas de Adesão Celular/metabolismo , Citomegalovirus/fisiologia , Enterovirus Humano B/fisiologia , Herpesvirus Humano 1/fisiologia , Antígenos de Histocompatibilidade Classe II/metabolismo , Antígenos de Histocompatibilidade Classe I/metabolismo , Epitélio Pigmentado Ocular/virologia , Animais , Células Cultivadas , Efeito Citopatogênico Viral , Regulação para Baixo , Técnica Indireta de Fluorescência para Anticorpo , Humanos , Molécula 1 de Adesão Intercelular/metabolismo , Camundongos , Epitélio Pigmentado Ocular/metabolismo , Coelhos , Molécula 1 de Adesão de Célula Vascular/metabolismoRESUMO
PURPOSE: We detected aqueous humor levels of substance P in patients with various grades of proliferative vitreoretinopathy and with uncomplicated rhegmatogenous retinal detachment. To evaluate the significance of the concentration of substance P at the time of surgery for retinal detachment for subsequent development of proliferative vitreoretinopathy, the latter patients also underwent fundoscopic control examination. METHODS: Using a highly specific and sensitive radioimmunoassay, the content of substance P in fresh samples of aqueous humor obtained by paracentesis was determined both in cataract controls and in patients with uncomplicated rhegmatogenous retinal detachment and with various grades of proliferative vitreoretinopathy. Retinal detachment patients underwent fundoscopic control examination 6 months after surgical reattachment. RESULTS: The mean concentration of substance P in cataract controls was 40.3 (+22.4) fmol/mg protein, in the retinal detachment group 61.9 (+/-13.9) fmol/mg protein and in proliferative vitreoretinopathy 335.2 (+/-24.8) fmol/mg protein, but no correlation between levels of the peptide and various grades of the disease was observed. Already at surgery for retinal detachment three in four patients who developed proliferative vitreoretinopathy presented with levels of substance P in the range of the disease. CONCLUSION: The concentration of substance P in aqueous humor is significantly high in patients with proliferative vitreoretinopathy in whom surgery is indicated. Furthermore, elevation of the peptide in retinal detachment that originates most obviously from a neurogenic mechanism may indicate initiation of processes associated with proliferative vitreoretinopathy, thus representing an indicator of significant risk for evolution of the disease at a very early time.
Assuntos
Humor Aquoso/metabolismo , Substância P/metabolismo , Vitreorretinopatia Proliferativa/metabolismo , Adulto , Catarata/metabolismo , Criocirurgia , Progressão da Doença , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Radioimunoensaio , Descolamento Retiniano/metabolismo , Descolamento Retiniano/cirurgia , Recurvamento da Esclera , Vitrectomia , Vitreorretinopatia Proliferativa/cirurgiaRESUMO
BACKGROUND: Different viruses have been reported to be involved in retinal diseases in animal systems. In humans, herpes simplex virus and cytomegalovirus have been found to cause retinal disease. Most of the studied viruses are neurotropic. In this study, the in vitro susceptibility of human retinal pigment epithelial cells (RPEC) to representative members of different groups of human pathogenic viruses was investigated. METHODS: Early cultures of RPE C - after two or three passages - were infected with the following viruses: herpes simplex virus (HSV) type 1, human herpesvirus 6 (HHV-6), Epstein-Barr virus (EBV), cytomegalovirus (CMV), adenovirus types 1 and 7, measles virus, parainfluenza virus and coxsackie virus B3. RESULTS: Cultures of RPE C could be infected with neurotropic viruses like HSV or measles virus as well as with typical respiratory viruses like parainfluenza or adenoviruses. Coxsackievirus, an enterovirus, replicated as well as human CMV, whereas EBV and HHV-6, two lymphotropic viruses, failed to infect RPE. CONCLUSION: These findings suggest that a variety of viruses, including those causing rather common illnesses, might be capable of inducing retinal lesions under certain circumstances due to haematogenous spread during the course of viraemia.
Assuntos
Vírus de DNA/crescimento & desenvolvimento , Epitélio Pigmentado Ocular/virologia , Anticorpos Monoclonais/imunologia , Anticorpos Antivirais/imunologia , Antígenos Virais/análise , Células Cultivadas , Efeito Citopatogênico Viral , Vírus de DNA/imunologia , Imunofluorescência , Humanos , Técnicas Imunoenzimáticas , Epitélio Pigmentado Ocular/citologiaRESUMO
Previous studies demonstrated that the frequency of donor-versus-host-reactive cytotoxic T-cell precursors (CTL-p) before allogeneic bone marrow transplantation (BMT) from matched unrelated donors correlates with the incidence of graft-versus-host disease (GvH-D). We investigated whether clinical manifestations of GvH-D after HLA-identical sibling BMT are accompanied by an increased frequency of minor histocompatibility antigen (HA)-specific CTL-p. We further asked whether changes of third-party-reactive CTL-p as a measure of overall immunocompetence are related to infectious complications frequently seen immediately after BMT. Eighteen patients (16 with an HLA-identical bone marrow graft, two with either one HLA-A or one HLA-DR mismatch) were studied. Limiting dilution analysis (LDA) was used to assess donor CTL-p frequencies against recipient pre-BMT, donor, and third-party targets in a follow-up study. Eight cases receiving HLA-identical marrow grafts never developed signs of GvH-D. Undetectable or very low frequencies (1/131,458) of minor HA-specific CTL-p were demonstrated pre-BMT. Two recipients, one of an HLA-A- and one of an HLA-DR-mismatched graft, exhibited low frequencies of recipient-specific CTL-p (1/66,920 and 1/85,577, respectively) before transplantation, which further decreased despite mild GvH-D grade I, or decreased within 3 months after grafting in the other case. Eight patients receiving HLA-identical grafts developed GvH-D. Recipient-specific CTL-p were less than 1/300,000 in five patients during limited GvH-D (four with grade I and one with grade II disease of the skin), but were detectable in three patients presenting with extensive GvH-D grades II to III and ranged from 1/7,993 to 1/210,108. The differences in post-BMT recipient-specific CTL-p frequencies between patients with GvH-D grades 0 to I (median, less than 1/300,000) and those with GvH-D grades II to III (median, 1/111,970) were statistically significant (P less than .05). Posttransplant lymphocytes from all 18 patients contained less than 1/300,000 CTL-p with specificity for donor targets. Comparison of third-party-reactive CTL-p frequencies between donor and post-BMT recipient lymphocytes showed a severe and long-lasting depletion subsequent to BMT, which was not related to infectious complications. Again, these differences reached the level of statistical significance (median CTL-p before BMT, 1/4,417; after BMT, 1/14,289; P less than .005).(ABSTRACT TRUNCATED AT 400 WORDS)
Assuntos
Transplante de Medula Óssea , Doença Enxerto-Hospedeiro/etiologia , Células-Tronco Hematopoéticas/imunologia , Tolerância Imunológica , Linfócitos T Citotóxicos/imunologia , Feminino , Antígenos HLA-A/análise , Antígenos HLA-DR/análise , Humanos , Masculino , Transplante HomólogoRESUMO
Interleukin 2 (IL-2) and gamma interferon (IFN-gamma) were determined in supernatants of mitogen- and antigen-driven cell cultures from patients with hepatosplenic or intestinal schistosomiasis. Skin reactivity was tested using a panel of eight recall antigens. Results were compared with those of uninfected local controls. In both schistosomiasis groups, IL-2 activity was reduced before treatment. In less than one third of the patients, schistosomal antigens elicited detectable IL-2 activity. IFN-gamma production was reduced more severely in hepatosplenic cases, in particular after stimulation by anti-CD3 monoclonal antibodies. After anti-schistosomal therapy with praziquantel, mitogen-induced IL-2 and IFN-gamma activities became normal within 3 months in intestinal schistosomiasis, and within 6 months in the hepatosplenic patient group. Results of in vivo delayed-type hypersensitivity tests paralleled those of in vitro lymphokine production. In conclusion, evidence is presented for severe, antigen-unspecific suppression of lymphokine production and skin reactivity against recall antigens. Anti-parasitic chemotherapy is shown to reverse the impairment of cell-mediated immune responses at the cytokine level.
Assuntos
Interferon gama/biossíntese , Interleucina-2/biossíntese , Praziquantel/farmacologia , Esquistossomose mansoni/imunologia , Linfócitos T/metabolismo , Adolescente , Adulto , Idoso , Antígenos de Helmintos/farmacologia , Criança , Feminino , Humanos , Hipersensibilidade Tardia/induzido quimicamente , Intestinos/imunologia , Fígado/imunologia , Masculino , Pessoa de Meia-Idade , Esquistossomose mansoni/tratamento farmacológico , Testes Cutâneos , Baço/imunologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologiaRESUMO
The production of interferons (IFNs), IFN-gamma, tumor necrosis factors (TNFs) and TNF-alpha (TNF-alpha) by peripheral blood mononuclear cells (PBMNCs) of untransfused and transfused, but otherwise untreated patients with severe aplastic anemia (SAA) was determined using bioassays and immunoassays. In untransfused and pretransfused SAA patients, spontaneous and lectin-induced production of these cytokines by PBMNCs was strongly enhanced. Cytokine production in untransfused SAA patients did not differ from that in pretransfused patients. Similar relative frequencies of activated (HLA-DR+) lymphocyte subpopulations present in the PBMNCs demonstrated cytokine overproduction per cells. Cytokine production was studied in three SAA patients before and after blood cell transfusions. Spontaneous and lectin-induced production of these cytokines was abnormally high and unaffected by blood transfusions. In another patient exhibiting abnormal cytokine production, the hematopoietic response to cyclosporin-A in vivo was accompanied by normalization of cytokine production in vitro. We conclude that overproduction of IFN-gamma and TNF-alpha by lectin-stimulated PBMNCs is an intrinsic abnormality of SAA unrelated to blood transfusions. Normalization of production of IFN-gamma and TNF-alpha accompanying a clinical response to cyclosporin-A may cautiously be taken as further evidence suggesting a pathogenetic role of cytokine overproduction in SAA.
Assuntos
Anemia Aplástica/metabolismo , Interferons/biossíntese , Fator de Necrose Tumoral alfa/biossíntese , Anemia Aplástica/terapia , Antígenos de Diferenciação de Linfócitos T , Transfusão de Sangue , Linfócitos T CD4-Positivos/imunologia , Antígenos CD8 , Antígenos HLA-DR/análise , Humanos , Interferon gama/biossíntese , Ativação Linfocitária , Linfócitos T/imunologiaRESUMO
Experimental animal and human in vivo studies have previously demonstrated the impact of exogenous administration of various cytokines on frequencies of circulating myeloid and LAK precursor cells. For the first time we investigated whether exogenous cytokines, in the absence of antigenic challenge, may also influence frequencies of circulating antigen-specific cytotoxic T-lymphocyte precursor cells. We further asked whether triggering of autoimmune pathways as has been reported for several cytokines can be confirmed on the cellular level by demonstration of induction of autoreactive CTL-p. Limiting dilution analysis was used to determine alloreactive CTL-p frequencies in 31 patients with nonhematologic diseases before and after short-term systemic treatment with either rIL-2 (4.8 x 10(6) IU/m2 bid), rIL-3 (2.5, 5.0 or 10.0 micrograms/kg qd), rGM-CSF (5 micrograms/kg qd), rIFN-gamma (200 or 400 micrograms qd), or IFN-alpha (3 or 5 x 10(6) IU qod). Simultaneously, autoreactive CTL-p frequencies were determined by split-well analysis in 25 of these patients. We found that rIL-2 significantly expands the circulating precursor pool of alloreactive CTL (p < 0.05). rIL-3 affected CTL-p frequencies in a dose-dependent fashion. Low and intermediate doses of rIL-3 did not exhibit significant effects, whereas 10 micrograms/kg rIL-3 led to expansion of alloreactive CTL-p in the same order of magnitude as did rIL-2. This effect was statistically significant when compared with rGM-CSF (p < 0.02), which apparently had no influence on alloreactive CTL-p frequencies. In contrast to rIL-2 and rIL-3, exogenous rIFN-gamma markedly reduced the circulating precursor pool of CTL. This again was statistically significant compared with rIFN-alpha (p < 0.03), which, like rGM-CSF, did not exhibit any effects on the level of alloreactive CTL-p. Frequencies of autoreactive CTL-p were invariably below the limit of detection in our system (< 1/300,000). In conclusion, these data demonstrate that (a) short-term systemic administration of rIL-2, rIL-3, and rIFN-gamma differently affects the clone size of circulating precursors of alloreactive CTL in man, while rGM-CSF and rIFN-alpha do not exhibit measurable effects, and (b) none of the cytokines administered is capable of uncovering detectable frequencies of autoreactive CTL-p.
Assuntos
Interferon gama/farmacologia , Interleucina-2/farmacologia , Interleucina-3/farmacologia , Linfócitos T Citotóxicos/efeitos dos fármacos , Autoimunidade , Humanos , Proteínas Recombinantes/farmacologia , Células-Tronco/efeitos dos fármacosRESUMO
To explore whether polymorphonuclear leukocytes (PMNL) are activated to the priming threshold through intraoperative blood salvage, and are thus able to induce endothelial damage, we investigated chemotactic response (n = 20) and respiratory burst (RB; n = 20) of PMNL without (basal respiratory burst, bPMNL-RB) and after in vitro stimulation with formyl-Met-Leu-Phe (fMLP-RB) and phorbol myristate acetate (PMA-RB). Blood was processed with a continuous autotransfusion device (CATS). Heparin (Heparin group) and sodium citrate (Citrate group) were used alternately as an anticoagulant for each half of the chemotaxis and RB studies. Comparison of measurements from the processed autologous erythrocyte concentrates (paEC) to pre- and intraoperative arterial blood samples showed no statistically significant difference for any test of PMNL functional responses in an orthopedic patient population. Analysis of intraindividual changes demonstrated a significantly increased bPMNL-RB (both groups, P = 0.0032; Heparin group, P = 0.0098), fMLP-RB (both groups, P = 0.0484; Citrate group, P = 0.0371), and PMA-RB (Citrate group, P = 0.002) in the paEC compared with intraoperative arterial samples, whereas the chemotactic response did not change. Nevertheless, median values of all RB measurements in the paEC were within the range of pre- and intraoperative values, indicating that PMNLs contained in the paEC are neither impaired nor activated to the priming threshold. The results confirm the clinical experience that intraoperative blood salvage is safe to use during major orthopedic surgery and questions the beneficial effect of special leukocyte-removing filters.