Intrahepatic lymphocyte subpopulations and HLA class I antigen expression by hepatocytes in chronic hepatitis C.

The lymphocyte subpopulations in the peripheral blood and liver were studied in 17 patients with chronic active hepatitis type C (CAH C) by immunoenzymatic and immunofluorescence techniques, using mono-specific T cell antibodies and other reagents. The peripheral blood subsets showed no significant differences between the patients with CAH C and normal controls. In the liver, CD8-positive cells were predominant over CD4- and Leu 7-positive cells. Leu 7-, CD4-, and CD11-positive lymphocytes were all few in number. HLA class I antigen was expressed diffusely on the cell surfaces of the hepatocytes. Serum levels of soluble interleukin 2 receptor (sIL2R) in the CAH C patients were significantly higher than in normal controls (p less than 0.01). In CAH C, sIL2R levels were higher during exacerbations than during remissions (p less than 0.01). These results suggest that cytotoxic T cells (CD8- positive, CD4-negative, and CD11-negative) may play an important role in the pathogenesis of hepatocyte injury in patients with CAH C.     

Serial observation of lymphocyte subpopulations and interleukin 2 production of T cells from patients with acute viral hepatitis and chronic active hepatitis

T cell subpopulations and interleukin 2 (IL-2) production of T cells in peripheral blood from patients with acute viral hepatitis (AVH) and chronic active hepatitis (CAH) were studied to elucidate the change of T cells functions during the exacerbation of viral hepatitis. The ratio of the number of CD4-positive cells to CD8-positive cells (CD:CD8 ratio) was increased in many patients with AVH. During exacerbation of CAH, the CD4:CD8 ratio was higher than that during remission (p less than 0.01), due to a decrease in the number of CD8-positive cells. IL2 production of T cells in AVH and CAH with bridging necrosis was higher than that of T cells in normal controls (p less than 0.01, p less than 0.05, respectively). T cells from patients with CAH produced more IL2 during exacerbation than during remission (p less than 0.01). IL2 production of T cells and the CD4:CD8 ratio (p less than 0.005, p less than 0.01). The change in T cell subpopulations in AVH and during exacerbation of CAH was found to induce an immunological condition, in which T cells easily produce IL2, which induces a proliferation of cytotoxic T cells.     

Immunological aspects of chronic hepatitis

Chronic active hepatitis (CAH) is a clinically and histologically defined syndrome which is aetiologically heterogeneous. Immune reactions are involved in almost all types of chronic inflammatory liver diseases. The host's immune system is thought to contribute significantly to the degree of liver cell destruction in chronic hepatitis B—HBcAg is regarded as a major target antigen. Auto-immune type CAH is a syndrome of unknown aetiology, a loss of tolerance against self antigens is thought to be a principal pathogenetic mechanism. At least three different subgroups of auto-immune type CAH can be distinguished by circulating auto-antibodies: antinuclear antibodies (ANA), smooth muscle antibodies (SMA), liver membrane auto-antibodies (LMA); liver-kidney-microsomal antibodies (LKM); and antibodies to a soluble liver antigen (SLA). The identification of auto-immune type CAH has clinical relevance since only auto-immune type CAH seems to profit from immunosuppressive therapy. A suppressor T cell defect was demonstrated in chronic hepatitis B and auto-immune type CAH. However, this defect could only be reversed by the addition of prednisone in vitro in auto-immune type CAH. Present research concentrates on the evaluation of the precise cellular mechanisms leading to liver cell destruction. In vitro cytotoxicity assays including autologous target cell systems have several drawbacks due to the use of peripheral blood lymphocytes and the questionable viability of the hepatocytes isolated from liver biopsies. Immunohistological studies using monoclonal antibodies revealed that T₈ positive T lymphocytes account for the majority of the inflammatory cell infiltrate. In addition, T cell clones derived from liver biopsies are mainly T₈ positive and show cytotoxic function in vitro. At present, little is known about the antigen specificity of these liver-derived T cell clones.     

The cellular infiltrate in the liver in auto-immune chronic active hepatitis: analysis with monoclonal antibodies

The mononuclear cell infiltrate in the liver was analyzed, using a panel of monoclonal antibodies (MAbs) of known specificity, in 10 patients with auto-immune chronic active hepatitis and, for contrast, in 14 with other types of chronic parenchymal liver diseases. In all cases, the mononuclear cell (MNC) infiltrate in the liver consisted mostly of T lymphocytes. Helper (Th) cells were more frequent than suppressor/cytotoxic T cells (Tsc) in the portal tracts and cirrhotic scar tissue, while Tsc were more common in the hepatic parenchyma. The number of Tsc cells in the parenchyma was greatest in patients with histologically active CAH and least in patients with quiescent cirrhosis. "Plasmacytoid" cells with the morphology of plasma cells, a hallmark of the MNC infiltrate in auto-immune CAH, were more frequent in histologically active CAH than in quiescent cirrhosis. These plasmacytoid cells were T200 + ve, and hence of bone marrow origin, but the majority expressed neither membrane nor cytoplasmic immunoglobulin nor any lineage-specific marker antigens, and hence did not fulfil criteria for B lymphocytes; however, these cells were positive for OKT10 and HLA DR. No difference was evident between the MNC infiltrate in the liver in auto-immune CAH and that in the other acute or chronic liver diseases studied, including HBV-associated CAH; hence immunohistological studies do not point to any pathological processes uniquely responsible for the pattern of hepatocyte damage seen in auto-immune CAH.     

Characterization of effector cells in lymphocytotoxicity to autologous hepatocytes in HBsAg-positive and autoimmune chronic active hepatitis (CAH)

Peripheral blood lymphocyte subsets involved in cytotoxicity to autologous hepatocytes have been characterized by isolation on antibody-coated Petri dishes in autoimmune and HBsAg-positive chronic active hepatitis (CAH). In autoimmune CAH and in HBsAg-positive CAH without HBcAg in liver tissue, cytotoxicity is sustained by non-T lymphocytes and is confined to M1-positive cells bearing Fc receptors: M1 cytotoxicity inhibition by adding aggregated IgG suggests that these cells are responsible for an antibody-dependent cell-mediated mechanism (ADCC). Moreover, when T-enriched fractions were separated in T4, T8 and 5/9 positive subsets, only the first one showed a significant cytotoxicity: T4 positive cells might act as cytotoxic T cells or might be involved in delayed type hypersensitivity (DTH) reactions. Cytotoxic T lymphocytes in HBsAg-positive CAH with HBcAg in liver tissue are confined in T8 positive subset, while helper/inducer T cells (T4 positive or 5/9 positive) seem to play an important role only in the induction of cell-mediated injury against hepatocytes. The inhibition of T cell-cytotoxicity by preincubating liver cells with monoclonal antibody (Mab) anti-HLA AB and not with Mab anti-HLA DR or aggregated IgG supports the involvement of the class I major histocompatibility complex (MHC) expressed on the hepatocyte surface.     

Immunoglobulin on the surface of isolated hepatocytes is associated with antibody-dependent cell-mediated cytotoxicity and liver damage

Hepatocytes isolated from patients with chronic liver disease are often covered by immunoglobulin. The aim of the present study was to establish whether this surface immunoglobulin (SIg) mediates liver cell damage. Freshly isolated hepatocytes from percutaneous liver biopsy of 16 patients with chronic active hepatitis (CAH) (6 HBsAg positive), 3 with HBsAg-positive chronic lobular hepatitis (CLH), 5 with HBsAg-positive chronic persistent hepatitis (CPH) and 12 with minor histological abnormalities (MHA) (5 HBsAg positive) were divided into two aliquots. One was studied for the presence of membrane-bound immunoglobulin and the third component of complement by direct immunofluorescence and the other was incubated, in an allogeneic cytotoxic assay, with peripheral blood mononuclear cells prepared from healthy volunteers as a source of effectors for antibody-dependent cell-mediated cytotoxicity (ADCC). Liver biopsies were scored for portal and parenchymal inflammatory activity. The percentage of SIg positive hepatocytes was significantly higher in patients with CAH (median 52.5%) than in patients with CLH/CPH (20.5%) or in patients with MHA (1%). Percentages of SIg-positive liver cells were significantly correlated with total liver biopsy scores and with both portal or parenchymal scores considered independently. SIg were found to belong to the IgG class in all groups of patients. When hepatocytes were cultured with normal human lymphocytes, allogeneic cytotoxicity values were significantly higher in patients with CAH (median 34%) than in patients with CLH and CPH (18%) or in those with MHA (12%). Percentage cytotoxicity was positively correlated with total biopsy scores and with portal activity but not with parenchymal activity, suggesting that ADCC might play a damaging role mainly in the portal areas.(ABSTRACT TRUNCATED AT 250 WORDS)     

Identification of intrahepatic lymphocyte subpopulations in patients with fulminant hepatitis by the immunoenzymatic technique, using monoclonal antibodies

Intrahepatic lymphocyte subpopulations were studied in 11 patients with fulminant hepatitis (FH) (of whom 9 cases died) by the immunoenzymatic technique, using monoclonal T cell specific antibodies and other reagents. In peripheral blood, the OKT4 positive cells: OKT8 positive cells ratio in FH was higher than that in normal controls. In liver tissue, OKT8 positive cells were the predominant type of T cells, and these cells were in broad contact with the surface of the hepatocyte. Leu7 positive, OKT4/4a positive and Leu 15 positive cells were scarce and did not contact the hepatocyte. These results suggest that cytotoxic T cells may play an important role in hepatocyte necrosis in patients with FH.     

Immunohistochemical Studies on Intrahepatic Lymphocyte Infiltrates in Chronic Type B Hepatitis, with Special Emphasis on the Activation Status of the Lymphocytes

To study the immunopathogenesis of chronic type B hepatitis, we used a panel of monoclonal antibodies to characterize the intrahepatic mononuclear cell infiltrates in 39 patients with various forms of chronic hepatitis induced by hepatitis B virus (HBV) and, for comparison, in 10 with non-A, non-B (NANB)-induced chronic hepatitis. In portal areas, the OKT4:OKT8 ratio reversed because of the relative increase of OKT8+ cells. The mean intraportal T4:T8 ratio was significantly lower in HBV-associated chronic active hepatitis (CAH) than in chronic persistent hepatitis induced by HBV or NANB viruses. OKT8+ cells were predominant in the infiltrates of periportal areas (piecemeal necrosis) and lobules. As to the activation status of the infiltrates, T10 was found much more frequently on mononuclear infiltrates of piecemeal necrosis and peripheral portion of portal areas in CAH cases, regardless of viral etiology, and its existence was correlated with the severity of CAH. Natural killer cells, killer cells, and B-cells played little role in the pathogenesis of hepatocytolysis. We conclude that T-cell cytotoxicity is the main mechanism of hepatocytolysis, either in lobules or in periportal regions, and that T10 antigen defines a group of cells which may play an important role associated with the formation of piecemeal necrosis.     

Cellular immune responses in the acute exacerbation of hepatitis B e antigen-positive type B chronic hepatitis

The compositions of lymphocytes in peripheral blood and liver biopsies from 29 patients with hepatitis B e antigen-positive type B chronic hepatitis were studied by an indirect peroxidase-labeled antibody method using monoclonal antibodies to surface antigens on pan T cells (Leu-1 +), cytotoxic/suppressor T cells (Leu-2a +), helper/inducer T cells (Leu-3a +), natural killer/killer cells (Leu-7 +), and B cells (Leu-10 +). In the peripheral blood during the acute exacerbation of chronic hepatitis B, the percentage of cytotoxic/suppressor T cells was decreased, and the ratio of helper/inducer to cytotoxic/suppressor cells was elevated corresponding to the peak of serum transaminase. In contrast, in liver biopsies obtained during acute exacerbation, numerous lymphocytes infiltrated sites of liver cell necrosis and were predominantly cytotoxic/suppressor cells. When compared with the liver biopsies obtained about 2 months after the peak of serum transaminase, cytotoxic/suppressor cells were significantly increased in those obtained during the acute exacerbation period. No significant change of the percentage of natural killer/killer cells was observed in either the peripheral blood or the liver during the acute exacerbation. These findings suggest that T cell cytotoxicity plays an important role in the mechanisms of liver cell damage in acute exacerbation of chronic hepatitis B.     

Interferon-gamma receptors on T cells in patients with chronic liver disease

Interferon-gamma (IFN-gamma) appears to be important for the activation of T cells, and its binding to IFN-gamma receptors on T cells is an essential step for its actions. We investigated the expression of IFN-gamma receptors on T cells in chronic liver disease using radioiodinated recombinant interferon-gamma binding assay, and by Scatchard analysis. The mean numbers of IFN-gamma receptors on T cells from controls, asymptomatic hepatitis B virus carriers (ASC), patients with chronic active hepatitis (CAH), and patients with liver cirrhosis (LC) were 2,205 +/- 497, 2,494 +/- 1,074, 1,925 +/- 735, and 1,666 +/- 653, respectively. The numbers of IFN-gamma receptors on T cells from the patients with LC were significantly smaller than those of controls (P less than 0.05). Kids of IFN-gamma receptor on T cells from control and patient groups were 2.3 4.8 x 10(-9) M, and there was no significant difference among the groups. The percentage of T cells reactive with OKT3, OKT4, or OKT8 was similar in control and patient groups. These findings suggest that the decrease in IFN-gamma receptors in LC is not related to the activity of the liver damage, but is associated with the severity of the underlying disease. The normal expression of IFN-gamma receptors on T cells from CAH may provide a reasonable basis for IFN-gamma therapy to type B CAH.     

Hepatitis B virus DNA in mononuclear blood cells. A frequent event in hepatitis B surface antigen-positive and -negative patients with acute and chronic liver disease

We have investigated 38 hepatitis B surface antigen (HBsAg)-positive and 34-negative patients with acute and chronic liver disease for the presence of hepatitis B virus (HBV) DNA in peripheral mononuclear blood cells. Among the HBsAg-positive subjects HBV DNA was detected in the mononuclear cells of asymptomatic HBV carriers (2/6), patients with acute hepatitis (8/8), chronic active hepatitis (18/21), and with hepatocellular carcinoma (2/3); the viral DNA sequences were also identified in the mononuclear cells of patients with HBsAg-negative acute hepatitis (2/3), chronic active hepatitis (5/15) and hepatocellular carcinoma (5/16), some of these showing no evidence of HBV by conventional serological markers. By contrast HBV DNA was not detected after resolution of the acute viral infection. For 7 patients different mononuclear cell-enriched subpopulations were assayed and the viral DNA was observed in T lymphocytes (both OKT4+ and OKT8+ enriched subsets) and/or in B enriched lymphocytes; the restriction DNA patterns showed in some patients a genetic organisation of the viral DNA similar to those observed in the liver (including free monomeric and oligomeric HBV DNA and results consistent with integrated viral sequences); however, no HBV DNA replicative forms were detected. These results show that the hepatitis B virus infection of mononuclear blood cells (including lymphoid cells) is a frequent event at all stages of the viral infection which might be related to immunological abnormalities observed in HBV carriers; in addition the mononuclear blood cells analysis may provide an insight to the liver cells status.     

Interleukin 2 receptor bearing T lymphocytes in patients with chronic liver disease

We investigated the role of interleukin 2 receptor expression (IL 2R) on T cell in chronic liver disease. IL 2R was determined by analysing T cell surface Tac antigen with anti-Tac, a monoclonal antibody that binds at or near the binding site for IL 2, using a fluorescence-activated cell sorter. The percentage of Tac⁺ cells in T cell fraction from peripheral blood mononuclear cells in unstimulated cultures was 7.9 ±2.1% (±SD) in controls. A similar value was obtained in asymptomatic carriers of HBsAg (ASC), in patients with chronic active hepatitis (CAH) and liver cirrhosis (LC). Upon stimulatin with recombinant IL 2, there was a small but significant increase in Tac⁺ cells. The percentages of Tac⁺ cells in IL 2-stimulated cultures were significantly lower in ASC (P<0.01), patients with CAH (P<0.01) and LC (P<0.05) as compared to controls (16.4 ±4.4%). Percentages of Tac⁺ cells after stimulation with phytohemagglutinin P (PHA-P) in ASC and CAH did not differ from controls (74.9 ±5.9%). Only patients with LC showed diminished Tac⁺ cells (P<0.01) compared to controls. During a 4-wk course of recombinant IL 2 therapy, a serial study on 5 HBeAg-positive patients with CAH was done, and the results showed that Tac⁺ cells were significantly diminished 2 wk (P<0.01) and 4 wk (P<0.05) after starting therapy in comparison with pretreatment levels in IL 2-stimulated cultures. OKT3⁺, OKT4⁺, OKT8⁺ cells in T cell culture in response to stimulation with PHA-P were significantly decreased in patients with CAH and LC when compared with controls. These results indicate that IL 2/ IL 2R system has a role on modulating immune resoponse in chronic liver disease.     

Study of T cell subsets in patients with cutaneous leishmaniasis

Summary The proportion of T lymphocyte populations was assessed using monoclonal antibodies (OKT 3, OKT 4, OKT 8) and spontaneous E-rosette tests with SRBC (for total and active TE cells) in 36 patients with cutaneous leishmaniasis subdivided according to the clinical variety. The T cell profile was normal in patients with simple cutaneous leishmaniasis of early ulcerative type whereas active TE cells and OKT 4 positive cells were reduced in some cases of late ulcerative type. A significant reduction of active TE cells and of OKT 4 positive cells (helper/inducerphenotype) and increase of OKT 8 positive cells (suppressor/ cytotoxic phenotype) was observed in peripheral blood of all patients with persistent active lesions and leishmaniasis recidivans. In patients with highly ulcerated persistent lesions a low proportion of active TE cells was also demonstrated in cellular extracts from dermal tissue. The results support the data obtained in experimental leishmaniasis that lack of helper/inducer cells and generation of suppressor T cells may be responsible for the development of chronic leishmaniasis.     

Active E rosette-forming cells in the peripheral blood of patients with chronic active hepatitis

E rosette-forming cells (E-RFC) and active E-RFC were studied in the peripheral blood in patients with chronic active hepatitis (CAH), chronic persistent hepatitis (CPH), and in control subjects. A significant reduction in active E-RFC (a subpopulation of T lymphocytes considered actively involved in cell-mediated immune reactions) was found in patients with untreated CAH, both HB_sAg positive or negative. In contrast, patients with immunosuppressive-treated CAH showed an increased relative number of active E-RFC. A significant increase in active E-RFC was demonstrable in other immunosuppressivetreated chronic inflammatory disorders. In CPH active E-RFC were not different from normal controls. The number of E-RFC showed a relative and absolute decrease in both CPH and untreated CAH. These studies demonstrate an increase in active E-RFC in immunosuppressive-treated CAH and suggest that prednisone and azathioprine may have a differential effect on T lymphocyte subpopulations.This study was supported in part by a grant from the Instituto Nacional de Investigaçào Cientifica.     

Decreased level of suppressor/cytotoxic T cells (OKT8+) in polymyalgia rheumatica and temporal arteritis: relation to disease activity

Separated peripheral blood mononuclear cells were analyzed by fluorescent microscopy with monoclonal antisera for T cells (OKT3+), helper/inducer T cells (OKT4+) and suppressor/cytotoxic T cells (OKT8+). Thirty-seven patients with polymyalgia rheumatica (PMR), 13 of whom had positive biopsies for arteritis, were studied and compared with 25 age and sex matched normal subjects. The percentages of OKT3+ and OKT4+ T cells were similar in the PMR group and controls, but percentage of OKT8+ T cells was significantly reduced in patients (14.8 +/- 6.8) compared with controls (22.1 +/- 6.3). Values of OKT8+ T cells were extremely low in untreated patients with active, acute disease (7.8 +/- 4.4%) and significantly lower than in prednisone treated patients with inactive disease (17.3 +/- 5.9). These findings indicate that low values of circulating OKT8+ T cells is a feature of PMR and is related to disease activity.     

Immunohistochemical characterization of hepatic tissue lymphocyte subpopulations in liver disease

Liver biopsies from 27 patients were studied by the indirect immunofluorescence and immunoperoxidase technique for relative distribution of B cells and T-cell subpopulations. T-cell subsets were defined for OKT4(+) (helper/inducer) and OKT8(+) (suppressor/cytotoxic) cells by using mouse hybridoma monoclonal antibodies. Patients with chronic active hepatitis and those with primary biliary cirrhosis showed marked relative increments in suppressor/cytotoxic OKT8(+) lymphocytes within hepatic lymphocytic infiltrates. Other patients with acute hepatitis or those with only reactive changes also showed a relative increment in OKT8(+) T lymphocytes within hepatic biopsy material. These findings suggest that tissue lymphocytic subpopulation increments in suppressor/cytotoxic T-cell subpopulations are commonly associated with hepatic lymphocytic infiltrates and may be related to disorders of immune regulation or expression in some of these disorders.     

Analysis of T cell subsets in the peripheral blood and synovial fluid of patients with rheumatoid arthritis by means of monoclonal antibodies.

In an attempt to define the immunoregulatory mechanisms operating in rheumatoid arthritis we have enumerated T cell subsets in the peripheral blood and synovial fluid of patients with this disease. The peripheral blood analysis revealed an elevation of the ratio of inducer T cells (OKT4 positive) to suppressor/cytotoxic T cells (OKT5 positive) in patients with clinically active rheumatoid arthritis when compared with normal persons. This was due to a reduction in the percentage of suppressor/cytotoxic T lymphocytes in these patients. The synovial fluid in rheumatoid arthritis differed from the peripheral blood in 2 respects. Firstly, synovial fluid was characterised by a lower helper: suppressor ratio due to an increased number of suppressor/cytotoxic cells, and, secondly, it contained an increased number of activated T cells bearing HLA DR antigens. The majority of these activated T cells belonged to the helper/inducer T cell subset.     

Effects of recombinant interleukin 2 on immunological effector cells of the peripheral blood in patients with HBe antigen-positive chronic hepatitis

Changes in peripheral blood immunological effector cells after systemic administration of recombinant interleukin 2 (rIL2) were studied in 14 patients with HBe antigen-positive chronic hepatitis. The patients were intravenously injected with rIL2 for 4 weeks, and the experiments were performed using mononuclear cells isolated from the peripheral blood during and after rIL2 administration. No significant changes in OKT4-positive cell population, OKT8-positive cell population, OKT4/OKT8 ratio and Leu7-positive cell population were detected during and after intravenous injection of rIL2. However, the natural killer (NK) cell and lymphokine-activated killer (LAK) cell activities significantly increased in the fourth week of rIL2 administration, while the K cell activity in the antibody-dependent cell-mediated cytotoxicity reaction, antibody response, lectin-induced lymphocyte transformation and IL1 production of LPS-stimulated monocytes were not affected. These results suggest that IL2 increases the NK cell and LAK cell activities in vivo.     

Disproportionate lymphoid cell subsets in thalassaemia major: the relative contributions of transfusion and splenectomy

The relative proportions of T-cell (OKT3-positive, OKT4-positive and OKT8-positive) and B-cell (SIg-positive) populations in peripheral blood obtained from 29 chronically transfused patients with beta-thalassaemia major were compared with those of 17 healthy controls. Changes attributable to blood transfusion and/or splenectomy are described. The percentage of OKT8-positive (T-suppressor) cells found in the thalassaemic patients increased linearly (P less than 0.001) with the number of units transfused, irrespective of splenectomy. The percentage of OKT4-positive (T-helper) cells varied inversely with increasing transfusion in nonsplenectomized patients while in those who were splenectomized no significant correlation was apparent. Thus, in both groups of patients the T4/T8 ratio declined in a transfusion-related manner. The splenectomized patients experienced a marked and persistent lymphocytosis due to an increase in the number of both T- and B-cells. When the results were expressed as percentages, the greatest increase occurred in the number of B-cells, this increase being unrelated to the number of transfusions received. None of the serum parameters usually associated with iron overload or abnormal liver function correlated with the observed increases in T-suppressor and SIg-positive cells. These findings corroborate reports that transfusion of blood products may lead to decreased T4/T8 ratios. However, none of the patients studied manifested clinical signs of acquired immune deficiency syndrome (AIDS). Accordingly, studies which define transfusion related AIDS on the basis of analyses with monoclonal antibodies must be viewed with caution.     

Peripheral blood CD4-mediated enhancement and CD8-mediated suppression in the presence of recombinant hepatitis B virus core antigen

The proliferative response of peripheral blood T cells to hepatitis B core antigen (HBcAg) was studied in hepatitis B patients. CD4+ T cells from patients with chronic active hepatitis type B (CAH-B) exhibited a significant proliferative response to HBcAg, especially in hepatitis B envelope antigen (HBeAg)-positive patients. In contrast, there was no apparent T cell reaction to HBcAg in patients with CAH non-A, non-B, HBeAg-positive healthy carriers and in healthy volunteers. The proliferative response to CD4+ cells to bacterial extracts of Escherichia coli was always insignificant in all patients and healthy volunteers. The CD8+ cells did not proliferate in response to HBcAg in any subject, even in the presence of autologous irradiated CD4+ responder cells. The CD8+ cells, preactivated with HBcAg and HBcAg-reactive irradiated autologous CD4+ cells, suppressed the proliferative response to autologous CD4+ cells to HBcAg but not the response to phytohemagglutinin in HBcAg-responder CAH-B patients. CD4-mediated HBcAg-specific enhancement and CD8-mediated HBcAg-specific suppression in the peripheral blood compartments of HBcAg-responsive CAH-B patients are possible.