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PubMed1992

Autoantibodies to T and B cell lines detected in serum samples from patients with systemic lupus erythematosus with lymphopenia and hypocomplementaemia.

Antibodies to lymphocytes in serum samples from 88 patients with systemic lupus erythematosus (SLE) and 15 normal control subjects were examined by a cell enzyme linked immunosorbent assay (ELISA) with four human T and B cell lines as antigens. The antibodies reacted with the Wa B cell line and the T cell lines P12 (CD4-, CD8+), Jurkat (CD4-, CD8-), and Hut78 (CD4+, CD8-). Antibody titres in serum samples from patients with SLE were higher than in those from normal control subjects. Titres of antibodies to P12 were correlated with titres of antibodies to Wa, Jurkat, and Hut78 in serum samples from patients with SLE. IgG antibodies to P12 were associated with lymphopenia and reduced haemolytic complement. By thin layer chromatography immunostaining, the antibodies in serum samples from two of 10 patients with SLE with high titres of IgG antibodies to P12 and lymphopenia were shown to react with three monosialoglycosphingolipids and two neutral glycosphingolipids from P12 cells. Antibodies to lymphocytes in serum samples from patients with SLE react with T and B cell lines, recognise a series of cell membrane glycosphingolipids and are associated with the lymphopenia and hypocomplementaemia typical of active disease.

Adult↗
PubMed2002

Lymphopenia in Wegener's granulomatosis. A new clinical activity index?

BACKGROUND: Significant lymphopenia is a prominent feature in systemic erythematous lupus, but has not been described in Wegener's granulomatosis (WG). We suggest from a retrospective analysis that lymphopenia may also be an index of WG disease activity. METHODS: Medical charts form 19 patients diagnosed with systemic active WG between 1990 and 2000 were reviewed retrospectively. All patients had crescentic glomerulonephritis and alveolar hemorrhage. Clinical and biological markers were reviewed at three different time points: diagnosis, time of relapse, and during remission. RESULTS: Average lymphocyte count was significantly lower at diagnosis and relapse than during remission times (p < 0.008 and p < 0.000002, respectively). During disease activity either at diagnosis and during relapses, ANCA titers were highly positive (> or =50 IU/ml) in 27.5% of patients (8/29). The corresponding lymphocyte counts were below normal (1,500/min(3)) in 28 of 29 patients (96.5%). In patients with either negative or weakly positive ANCA, mean lymphocyte count was 728.5, 744.2 and 2,551/ml at diagnosis, during relapse and remission times, respectively. There was a clear negative correlation between the lymphocyte count and disease activity. CONCLUSION: Lymphopenia appears to be a good marker of WG activity. This index might be useful in all patients including those with negative ANCA.

Adult↗
PubMed2004

Interleukin-7 deficiency in rheumatoid arthritis: consequences for therapy-induced lymphopenia.

We previously demonstrated prolonged, profound CD4+ T-lymphopenia in rheumatoid arthritis (RA) patients following lymphocyte-depleting therapy. Poor reconstitution could result either from reduced de novo T-cell production through the thymus or from poor peripheral expansion of residual T-cells. Interleukin-7 (IL-7) is known to stimulate the thymus to produce new T-cells and to allow circulating mature T-cells to expand, thereby playing a critical role in T-cell homeostasis. In the present study we demonstrated reduced levels of circulating IL-7 in a cross-section of RA patients. IL-7 production by bone marrow stromal cell cultures was also compromised in RA. To investigate whether such an IL-7 deficiency could account for the prolonged lymphopenia observed in RA following therapeutic lymphodepletion, we compared RA patients and patients with solid cancers treated with high-dose chemotherapy and autologous progenitor cell rescue. Chemotherapy rendered all patients similarly lymphopenic, but this was sustained in RA patients at 12 months, as compared with the reconstitution that occurred in cancer patients by 3-4 months. Both cohorts produced naive T-cells containing T-cell receptor excision circles. The main distinguishing feature between the groups was a failure to expand peripheral T-cells in RA, particularly memory cells during the first 3 months after treatment. Most importantly, there was no increase in serum IL-7 levels in RA, as compared with a fourfold rise in non-RA control individuals at the time of lymphopenia. Our data therefore suggest that RA patients are relatively IL-7 deficient and that this deficiency is likely to be an important contributing factor to poor early T-cell reconstitution in RA following therapeutic lymphodepletion. Furthermore, in RA patients with stable, well controlled disease, IL-7 levels were positively correlated with the T-cell receptor excision circle content of CD4+ T-cells, demonstrating a direct effect of IL-7 on thymic activity in this cohort.

Alemtuzumab↗
PubMed1999

Therapeutic and prognostic implications of peripheral blood lymphopenia in patients with Hodgkin's disease.

Patients with Hodgkin's disease (HD) are known to have peripheral blood lymphopenia, but the prognostic significance of this observation and its implication on immune therapy remain controversial. We determined the peripheral blood lymphocyte (PBL) counts and their subsets of 238 newly diagnosed patients with HD referred to our institution, and the quantitative changes of B, T, and natural killer cells were correlated with the patients' clinical variables. The mean white blood cell count increased steadily with advancing disease stage. In contrast, the mean absolute PBL count and its CD4, CD8, and CD3-/CD56+/CD16+ subsets, after an initial increase in stage I, steadily decreased with advanced HD stages. The mean CD20 lymphocyte count decreased steadily with advancing stage without an initial increase. Prognostic factor analysis was determined in 196 patients adequately treated with modern therapies. Neither the absolute PBL count, nor CD4, CD8, or CD20 counts correlated with shorter disease free survival. In this study, the decline in total PBL count or in its subsets in HD patients did not correlate with shorter disease free survival. Because peripheral blood lymphopenia of HD correlated with advanced clinical stage but had no independent prognostic significance, we propose that this peripheral blood lymphopenia is likely to be due to lymphocyte trafficking and homing to the diseased nodes rather than due to an absolute quantitative deficiency. Thus, strategies to improve lymphocyte functions in HD patients should continue to be explored therapeutically.

Adolescent↗
PubMed2005

Effects of increasing IL-7 availability on lymphocytes during and after lymphopenia-induced proliferation.

IL-7 is critically involved in regulating peripheral T cell homeostasis. To investigate the role of IL-7 on lymphopenia-induced proliferation of polyclonal lymphocytes, we have transferred CFSE-labeled cells into a novel T-lymphopenic, IL-7-transgenic mouse line. Results obtained indicate that T and B cells do not respond in the same way to IL-7-homeostatic signals. Overexpression of IL-7 enhances proliferation of both CD4(+) and CD8(+) T cells but with distinctly temporal effects. Expansion of naturally arising CD4(+)-regulatory T cells was like that of conventional CD4(+) T cells. IL-7 had no effect on B cell proliferation. By immunohistology, transferred T cells homed to T cell areas of spleen lymphoid follicles. Increasing IL-7 availability enhanced T cell recovery by promoting cell proliferation and reducing apoptosis during early stages of lymphopenia-induced proliferation. Taken together, these results provide new insights into the pleiotropic effects of IL-7 on lymphopenia-induced T cell proliferation.

Adoptive Transfer↗
PubMed2002

Lymphopenia in dialysis patients: a preliminary study indicating a possible role of apoptosis.

Lymphopenia is a common finding in dialysis patients. Since infection rate and mortality associated with infection are high in dialysis patients, lymphopenia may be one of the contributing factors. In the present study, we evaluated the mechanism responsible for lymphopenia in these patients. Lymphocytes isolated from dialysis patients showed increased apoptosis (p < 0.001) when compared to lymphocytes isolated from healthy subjects (healthy subjects, 0.5 +/- 0.2% vs. dialysis patients, 8.8 +/- 0.7% apoptotic cells/field). Sera from dialysis patients promoted lymphocyte apoptosis in a time- and dose-dependent manner. These sera also enhanced lymphocyte DNA fragmentation into multiple integers of 180 base pairs in the form of a ladder pattern. Cellulose acetate membranes promoted T cell apoptosis when compared to polysulfone membranes and to control. Cellulose acetate dialysis membranes also appear to promote lymphocyte FasL expression. Similarly, dialysis sera enhanced T cell Fas as well as FasL expression. Neither the cellulose acetate nor polysulfone membranes could induce FasL expression on B cells. Similarly, dialysis sera failed to induce FasL expression on B cells. On the other hand, anti-FasL antibodies attenuated dialysis sera-induced apoptosis in T as well as B cells. Interestingly, dialysis serum showed a 5-fold increase in FasL content when compared with control serum. These results suggest that dialysis-associated factors can induce autocrine death in T cells but the help of activated T cells is required to induce death in B cells.

Adult↗
PubMed2001

[Immunomodulatory treatment of lymphopenia after infectious mononucleosis].

Persistent lymphopenia of various intensity has been noted in 45% of persons who had a history of infectIous mononucleosis. The group consisted od 500 patients, (236 males and 264 females). In all of them the diagnosis of mononucleosis had been based on the characteristic clinical signs and symptoms and changes in the blood picture and confirmed by the non-specific and/or specific serologic tests. In 33 persons (10 males and 18 females) the total number of lymphocytes varied from 884 to 992 per 1 cmm, the distribution being as follows: B lymphocytes--146 to 198, CD4--482 to 645 and CD8--245 to 364 per 1 cmm. 18 persons (18 males and 10 females) were given thymosine (TFX) subcutaneously for 30 days in the dose of 0.02 g daily, the remaining 15 (7 males and 8 females) received 3.0 g of isoprinosine per day for the same period. The total lymphocytes count and that of B, CD4 and CD8 was performed before and after the treatment and then followed once a month until 180 days since the treatment had been started. The TFX therapy was repeated after 8-12 months since the end of the first course in 3 patients and that with isoprinosine in 4. The strategy and the examination pattern were the same as before, control examinations being performed every 6 months and final analysis was done after 5 years of follow-up. Among the 33 patients who received immunomodulating treatment, normalisation of the lymphocytes count appeared in 24 (64%). Among the 12 persons with less pronounced lymphopenia, who did not received any treatment, spontaneous normalisation appeared in 5 (40%). It may be therefore assumed, that in persons with the history of infectious mononucleosis with persistent marked lymphopenia, thymosine and isoprinosine may be used in the therapy as additional immunomodulators.

Acute Disease↗
PubMed2005

[New strategy of cancer immunotherapy: irradiation or chemotherapeutics-induced lymphopenia combined with immune reconstitution and tumor vaccine].

OBJECTIVE: To test whether vaccination performed during irradiation or chemotherapeutics-induced lymphopenia-driven T cell proliferation could augment the antitumor immunity. METHODS: The study composed of two parts, investigating the anti-tumor efficacy of performing tumor vaccination during early immune reconstitution period following sublethal total body irradiation and cyclophosphamide (Cy)-induced lymphopenia, respectively. Mice were subsequently reconstituted with naïve splenocytes from syngeneic mice and were named RLM (Reconstituted lymphopenic mice). Immunization/vaccination (F10) and adoptive immunotherapy (D5-G6) were used to explore anti-tumor immune responses in vaccinated irradiation/RLM and vaccinated Cy/RLM, respectively. Both normal C57BL/6 mice and RLM were vaccinated with irradiated, weakly immunogenic F10 melanoma cells and subsequently challenged with F10 cells. In addition, to determine the role of CD4(+) and CD8(+) T cells in the protective anti-tumor immune response, irradiation/RLM were depleted of these subpopulations by administration of the appropriate mAb around challenge. In the second part, adoptive immunotherapy was used to evaluate the anti-tumor immune responses under chemotherapeutics-induced lymphopenic condition. Both normal mice and RLM (Cy-treated) were vaccinated with GM-CSF-modified D5 melanoma cells (D5-G6) and tumor vaccine draining lymph nodes (TVDLN) were harvested 9-10 days later. Effector T cells were generated in vitro from TVDLN cells and adoptively transferred to mice bearing 3-day pre-established pulmonary metastases (D5). Recipient mice were sacrificed 2 weeks later after tumor inoculation and pulmonary metastases were enumerated. RESULTS: Significantly greater protection was induced in vaccinated irradiation/RLM, compared to vaccinated normal mice (63.2% vs 16.7%). Protective immunity in RLM depended on CD8(+) T cells. Increase in the interval between reconstitution and vaccination significantly decrease the protection. Effector T cells generated from vaccinated Cy-treated RLM demonstrated significantly higher in vivo anti-tumor efficacy over those of vaccinated normal mice. CONCLUSION: This study suggests that vaccination of RLM could elicit augmented antitumor immunity compared to normal hosts, highlighting the potential clinical benefit of performing tumor vaccination during irradiation or chemotherapeutics-induced lymphopenia in cancer patients.

Animals↗
PubMed1995

[Cutaneous and lymphatic cryptococcosis after transient lymphopenia in an immunocompetent patient].

INTRODUCTION: Cryptococcosis is an opportunistic infection, that rarely occurs in immunocompetent patients. CASE REPORT: We report a case of a 82 year-old woman who suffered from a bacterial pneumonia associated with lymphopenia. During the hospitalisation, she developed a cutaneous and ganglionnary cryptococcosis. No other cause of immunosuppression was found. The lymphopenia disappeared with the healing of the pneumonia treated with systemic antibiotics. Treatment with fluconazole was effective in 2 months on the cryptococcosis. COMMENTS: To our knowledge, this is the first case of cryptococcosis after a transitory lymphopenia, occurring in a immunocompetent patient.

Aged↗
PubMed1966

Occurrence of lymphopenia in heart failure.

The incidence of lymphopenia and eosinopenia in 10 patients admitted to hospital in heart failure was compared with that in 11 ;cold' admissions and 10 with acute diseases admitted via the Casualty Department. Plasma cortisol determinations were made simultaneously. A significant difference was found between the heart failure group and the ;cold' controls in respect of lymphopenia, eosinopenia, and cortisol levels. The ;acute' control patients showed an overlap with both groups. It is concluded that this lymphopenia is part of a response to stress.Seventy-two hours after admission there was no significant change in these values although the figures suggest the beginning of a return to normal.

Aged↗
PubMed1999

The lymphopenia mutation of the BB rat causes inappropriate apoptosis of mature thymocytes.

BB rats develop autoimmune diabetes mellitus at a high frequency. A key factor in the development of the disease is an autosomal recessive mutation determining peripheral T cell lymphocytopenia. Previous studies have suggested that the lymphopenia could be caused by increased cell death. Here we demonstrate that the lyp mutation dramatically reduces the in vitro lifespan of the TCRhi single-positive thymocytes and peripheral T cells, without abolishing their capacity to proliferate. The reduced lifespan is due to an increased rate of apoptosis, and is detected in single-positive thymocytes displaying characteristics of cells which have undergone positive selection. The cell death defect does not affect the in vitro lifespan of peripheral B cells. Interestingly, stimulation can rescue peripheral lyp/lyp T cells from immediate cell death. We propose that the lymphopenia mutation prevents the accumulation of a normal T cell pool, including regulatory subsets, without preventing the activation and proliferation of reactive T cells, thereby creating conditions appropriate for the development of uncontrolled autoimmune responses.

Animals↗
PubMed1977

Lymphopenia caused by cranial irradiation in children receiving craniospinal radiotherapy.

The peripheral blood changes were studied in 67 children who received craniospinal irradiation for posterior fossa tumors. At the completion of a cranial dose of about 3500 rad to the whole brain port, the lymphocytes were reduced to 858/mm3 rom 3084/mm3 preoperatively. The counts of the remaining leukocytes stayed at a level somewhat higher than preoperatively; the eosinophils rose to 288/mm3 from 125/mm3. With the initiation of the spinal field irradiation, which included a large proportion of the total bone marrow, the numbers of all the leukocytes decreased rapidly; the observed leukopenia was mainly secondary to neutropenia. A mechanism that was operating to restore the number of leukocytes became manifest immediately after the completion of radiotherapy, though the number of lymphocytes had not been totally restored to the preoperative level 6 years later. Irradiation of the lymphocytes that circulate through the vascular bed can explain the lymphopenia observed during cranial radiotherapy. Mild leukopenia observed in patients receiving radiotherapy through a relatively small port may be secondary to lymphopenia, and this does not necessarily indicate impaired bone marrow reserves.

Adolescent↗
PubMedDate not supplied

Association of cold-reactive antilymphocyte antibodies with lymphopenia in systemic lupus erythematosus.

In a prospective study 26 of 29 patients with systemic lupus erythematosus had cold-reactive antilymphocyte antibodies cytotoxic for autologous lymphocytes and lymphocytes from normal subjects. The level of antilymphocyte antibodies was highly correlated, by linear regression analysis, with lymphopenia in these patients. The data suggested that both the avidity and the concentration of these antibodies were important determinants in this relationship. A clear association between increased antilymphocyte antibody activity and exacerbation of SLE was demonstrated. Apart from lymphopenia, however, neither type of clinical manifestation nor any particular serologic abnormality appeared to be related to the presence of antilymphocyte antibodies.

Antibodies↗
PubMed2004

CD4 lymphopenia as a risk factor for febrile neutropenia and early death after cytotoxic chemotherapy in adult patients with cancer.

BACKGROUND: Lymphopenia is frequently observed in patients with cancer and correlates with the risk of febrile neutropenia and early death after chemotherapy. The phenotype of the depleted lymphocyte populations was investigated in the current study. METHODS: Peripheral blood lymphocyte subsets (CD3, CD4, CD8, CD19, CD56) were quantified on Day 1 using fluorescence-activated cell sorting in a prospective study of 213 patients with cancer treated with chemotherapy in a single oncology ward during 12 months. Correlations between lymphocyte phenotype, clinical characteristics, and the risk of febrile neutropenia and early death within 31 days after chemotherapy were investigated in univariate and multivariate analyses. RESULTS: Total lymphocyte count and CD3, CD4, and CD8 lymphocyte subsets were significantly lower in patients who experienced febrile neutropenia. Total lymphocyte count and CD3, CD4, CD8, CD19, and CD56 lymphocyte subsets were significantly lower in patients who died within 31 days after chemotherapy. Using logistic regression, CD4 lymphopenia (< 450/muL; odds ratio [OR] = 2.9, 95% confidence interval [CI] = 1.5-5.9) and the dose of chemotherapy (OR = 3,9, 95% CI = 2.0-7.8) were both identified as independent risk factors for febrile neutropenia. Fifty-four percent of patients with both risk factors experienced febrile neutropenia. CD4 lymphocyte count < 450/muL was also an independent risk factor for early death (OR = 7.7, 95% CI = 1.7-35). Thirteen percent of patients with a CD4 lymphocyte count </= 450/muL died within 31 days after chemotherapy. Eighty-seven percent (14 of 16) of patients who died before Day 31 had a CD4 lymphocyte count < 450/muL. CONCLUSIONS: A low CD4 count was an independent risk factor for febrile neutropenia and early death in patients receiving cytotoxic chemotherapy.

Adolescent↗
PubMed1995

Relationship between susceptibility to apoptosis and Fas expression in peripheral blood T cells from uremic patients: a possible mechanism for lymphopenia in chronic renal failure.

Chronic renal failure (CRF) is often complicated by lymphopenia, which may be partly responsible for immune deficiency. We hypothesized that lymphopenia in CRF might result from apoptosis of T cells in vivo. To elucidate the involvement of Fas antigen which mediates apoptosis, we analyzed Fas expression on peripheral blood T cells in uremic non-dialyzed (non-HD) patients and hemodialysis (HD) patients. T cells from both uremic groups expressed Fas with higher intensity than control T cells. When two uremic groups were compared, Fas intensity on T cells was significantly higher in non-HD patients than in patients on HD. Moreover, uremic T cells were shown to undergo accelerated apoptosis when cultured in vitro, in correlation with Fas expression. Our results suggest that T cells in CRF may undergo apoptosis by the Fas system and that hemodialysis treatment has beneficial effects in the light of the inhibition of T cell apoptosis.

Apoptosis↗
PubMed1997

Dietary restriction in rhesus monkeys: lymphopenia and reduced mitogen-induced proliferation in peripheral blood mononuclear cells.

Dietary restriction (DR) markedly extends mean and maximal life span, and retards the rate of biological aging in rodent models; however, it is unknown if these results occur in primate species. The purpose of the current study was to investigate selected immunologic outcomes in Rhesus monkeys subjected to DR for a period of seven years. Similar to observations in mice on DR, lymphopenia occurred in the restricted monkeys. Compared to normally fed controls, the mitogen-induced proliferative responses of peripheral blood mononuclear cells (PBMC) were reduced in monkeys subjected to DR very early in life (up to 1 year), but not in others restricted in young adulthood (3-5 years). These data indicate that lymphopenia is a shared occurrence in rodents and primates on DR. However, the mitogen-induced proliferative data accumulated in rodents and primates cannot now be compared because PBMC have not been studied long enough or in comparable detail in primates fed restricted diets.

Aging↗
PubMed1997

The lymphopenia (lyp) gene controls the intrathymic cytokine ratio in congenic BioBreeding rats.

The lymphopenia gene (lyp) on rat chromosome 4 is closely linked to autoimmune diabetes in the BioBreeding (BB) rat. Lyp controls the number of peripheral lymphocytes by reducing T cells of the RT6+ phenotype by almost 90%. Following nine cycle of marker-assisted cross-intercross breeding we have developed congenic lyp/lyp, lyp/+ and +/+ (wildtype) rats on the background of DR rats. Prediabetic and insulitis free lyp/lyp, lyp/+ and +/+ rats were used to determine the effect of lyp on cytokine expression in the thymus. In situ hybridization of thymus cryosections showed that the interferon gamma (IFN gamma) mRNA expression was highest in lyp/lyp rats and the hybridization signal was restricted to the medullary compartment. The frequency of IFN gamma and interleukin (IL)-10 mRNA expressing cells in isolated thymocytes determined by quantitative image analysis, demonstrated an increased IFN gamma: IL-10 ratio in thymocytes from lyp/lyp homozygotes compared to lyp/+ and +/+ rats. This confirmed a lyp gene dose-dependent segregation of the IFN gamma high phenotype. Recombinant human glutamic acid decarboxylase (GAD65) increased the number of IFN gamma and IL-10 mRNA expressing thymocytes after in vitro culture. We conclude that the quantitative ratio of cytokine producing thymocytes is associated with the lyp genotype. These potentially autoreactive thymocytes may explain the establishment of beta-cell directed autoimmunity in the BB rat despite peripheral lymphopenia.

Animals↗
PubMed1999

Mapping of caspase-2 in the rat and its exclusion as a candidate gene for lymphopenia.

Caspase-2 is a member of the caspase family of cystein proteases involved in programmed cell death or apoptosis. Functional and genetic data suggest it as a candidate gene for lymphopenia (Lyp)-a susceptibility gene for rat diabetes-which is responsible for the T-cell lymphopenia in the diabetes-prone BB rat. Firstly, there is a higher frequency of apoptosis among recent thymic emigrants in the diabetes-prone BB rat than in the non-lymphopenic diabetes-resistant BB rat. Secondly, caspase-2 maps close to Tcrb on mouse Chromosome (Chr) 6, while Lyp is closely linked to Tcrb on the homologous rat Chr 4. In this paper, we report genetic fine-positioning and radiation hybrid mapping of caspase-2 in the rat. Both methods positioned caspase-2 to rat Chr 4 between markers Prss1 and D4Mit5. Since Lyp maps distally to D4Mit5, between markers D4Rat75 and Npy, we exclude caspase-2 as a candidate gene for Lyp.

Animals↗