天然HBV免疫的供体的异体骨髓移植即骨髓干细胞移植是效果最佳而又最为昂贵又极不切实际的HBV根治方法
----谈治疗性复合HBV系列疫苗的疫苗组方设计
HBV感染者因没有正常的抗HBV免疫功能，故不宜作BMT的供体，否则可致受体HBV感染（参考文献1-3）。但又有不少报导（参考文献3-14），HBV感染者受体如采用天然HBV免疫的供体的骨髓血/干细胞进行骨髓移植（ bone marrow transplant，BMT）则因过继了供体的免疫功能如APC/DC和CD4+/TH功能，则HBV可被清除而抗HBS抗体转阳。研究深入后发现其过继免疫除与天然HBV免疫的供体的HBVC区抗原特异性CD4+过继到受者体内有关外，还与骨髓其他细胞（APC/DC）有关（参考文献5~6，15）。
虽然天然HBV免疫的供体的异体骨髓移植即骨髓干细胞移植治疗HBV感染疗效显著，但不可否认，广泛开展/进行天然HBV免疫的供体的异体骨髓移植即骨髓干细胞移植是极其困难的，首先费用大（20-30万最少），其次MHC/HLA配对合适者难找，而又同时满足天然HBV免疫和MHC/HLA配对合适二个条件的则更难找。因此天然HBV免疫的供体的异体骨髓移植即骨髓干细胞移植是效果最佳而又最为昂贵又极不切实际的HBV根治方法。
采用药物激活HBV感染者的HBV特异性的免疫感应与效应功能的治疗性复合HBV系列疫苗，为替代天然HBV免疫的供体的异体骨髓移植而达到清除HBV的目的，为此治疗性复合HBV系列疫苗应考虑激活HBV特异性的免疫感应与效应功能的诸多药物与HBV疫苗抗原相结合，如激活免疫感应APC/DC功能的有GM-CSF等，而激活TH和CTL及B细胞以及NK、NK-T等免疫效应细胞功能的有牛磺酸等，而HBV疫苗抗原应包括HBS区、前S1区、前S2区及HBV C区。
1）Ireland J, Hino K, Lau GK, Cheng CC, Carman WF. Failed adoptive immunity transfer: reactivation or reinfection? J Viral Hepat 1999 Jan;6(1):73-8
A 26-year-old female bone marrow transplant (BMT) recipient was hepatitis B surface antigen (HBsAg) and hepatitis B e antibody (HBeAb) positive. The donor, her human leucocyte antigen (HLA)-compatible sister, was HBsAg negative but hepatitis B surface antibody (HBsAb) and hepatitis B core antibody (HBcAb) positive. Twelve weeks post-BMT the patient became HBsAg negative, as determined using a monoclonal antibody-based assay. At 16 weeks post-BMT, HBsAg became undetectable by monoclonal and polyclonal immunoassay with seroconversion to HBsAb; however, at 24 weeks post-BMT the patient again became HBsAg positive. Both the recipient and the donor were retrospectively tested by hepatitis B virus (HBV) polymerase chain reaction (PCR) and found to be positive. The recipient displayed variants at amino acids 4 and 47 of the surface (S) gene prior to BMT. These mutations were not detected 32 weeks post-BMT when the S gene sequence was identical to that of an adr prototype. The donor was found to have four unique amino acid substitutions at positions 30, 98, 101 and 210 of the S gene. However, in vitro-expressed HBsAg from the donor was detected by commercial kits and an immunofluorescence assay, indicating that antigenic alteration did not explain HBsAg negativity. This donor highlights the value of PCR as the gold standard test for current HBV infection. It also demonstrates that discordance between two commercial HBsAg assays may not always be caused by antigenic variants. The second episode of hepatitis may theoretically have been caused by reactivation, selection of an escape mutant by HBsAb, reinfection or recombination. We suggest it was reactivation because none of the donor variants was seen in the recipient post-BMT.
因供体是一HBVS区变异株，该HBV感染者的受体（病人）BMT后，故HBV感染者的受体出现一过性HBS阶段AG消失后，因其过继其供体（HLA/MHC相容性妹妹）的异常免疫（免疫压力偏倚而致HBV S区变异而HBVDNA仍阳性）功能，仍不能最后清除HBV而复HBS AG阳性。但受体没有过继其供体的HBV变异株。-----说明HBV感染者因没有正常的抗HBV免疫功能，故不宜作BMT的供体。
2） Locasciulli A, Alberti A, Bandini G, Polchi P, Arcese W, Alessandrino P, Bosi A, Testa M, Bacigalupo A. Allogeneic bone marrow transplantation from HBsAg+ donors: a multicenter study from the Gruppo Italiano Trapianto di Midollo Osseo (GITMO).Blood 1995 Oct 15;86(8):3236-40
Hepatitis B virus (HBV)-infected individuals are occasionally used as donors for bone marrow transplantation (BMT). We studied the rate of HBV infection and the clinical expression of the associated liver disease in patients receiving marrow from HBsAg+ donors. We performed a retrospective survey in 14 BMT units in Italy in which all BMTs performed between 1984 and 1994 were reviewed and those involving HBsAg+ donors were identified. Donors and recipients were analyzed for HBV markers and liver disease. A total of 24 of 2,586 patients (0.9%) had received an HBsAg+ marrow. HBsAg became detectable in 22% of pre-BMT HBsAg- patients, but only 5.5% became chronic HBsAg carriers. Antigenemia developed more frequently in anti-HBs- compared with anti-HBs+ patients independently of passive prophylaxis with hyperimmune anti-HBs Ig, although the difference was not significant. Severe liver failure with death occurred in 21% of patients, which was a value greater than that generally observed after BMT in our units (3.7%). Patients with an anti-HBe+ donor had higher frequency of liver failure (28% v 0%) and alanine aminotransferase peaks as compared with those of patients with an HBeAg+ donor. Liver failure was not observed in anti-HBs+ recipients. The use of HBsAg+ donors, particularly if anti-HBe+, increases the risk of severe liver disease in BMT recipients. Anti-HBs positivity may prevent severe liver damage.
HBV感染者因没有正常的抗HBV免疫功能，故不宜作BMT的供体。
3）Liang R, Lau GK, Kwong YL.Chemotherapy and bone marrow transplantation for cancer patients who are also chronic hepatitis B carriers: a review of the problem.J Clin Oncol 1999 Jan;17(1):394-8
In places where hepatitis B virus (HBV) infection is endemic, it is often necessary to give chemotherapy to or perform bone marrow transplantation for cancer patients who are also chronic HBV carriers. When standard chemotherapy was given to lymphoma patients, elevation of liver transaminases was observed in nearly half of those who were chronic HBV carriers. Ten percent of them became jaundiced, and the overall liver-related mortality was about 5%. There is currently no reliable way to predict the severity of HBV reactivation after chemotherapy. The risk is probably higher when the chemotherapy used is significantly immunosuppressive and the viral load in the liver is high. Different strategies have been used in an attempt to reduce the risk of HBV reactivation after chemotherapy, but they have not been very successful. Further studies will be required to determine the impact of newly available antiviral agents that are active against HBV. Recipients who are carriers of HBV or who receive hepatitis B surface antigen (HBsAg)-positive marrow are at increased risk of hepatitis B-related morbidity and mortality after bone marrow transplantation (BMT). There is evidence to suggest that prophylactic use of an active antiviral agent, such as famciclovir, may result in a significant decrease in the incidence and severity of HBV reactivation after BMT. Sustained serologic clearance of chronic HBV infection has also been reported in many HBsAg-positive marrow recipients receiving hepatitis B surface antibody-positive marrow from their allogeneic donors. There seems to be a transfer of both humoral and cellular immunity against HBV from donors to recipients. Further prospective studies are required to define the best approach to manage HBsAg-positive cancer patients receiving chemotherapy or BMT. It is recommended that all cancer patients be checked for their hepatitis B status before receiving chemotherapy or a bone marrow transplant, especially if they reside in or come from endemic areas of HBV infection.
HBV感染者因没有正常的抗HBV免疫功能，故不宜作BMT的供体，否则致受体HBV感染；但采用HBS AB阳性受体的骨髓或干细胞进行BMT则又使不少HBV感染者的HBV得以清除而治疗HBV感染。
4）Ilan Y, Nagler A, Adler R, Tur-Kaspa R, Slavin S, Shouval D.Ablation of persistent hepatitis B by bone marrow transplantation from a hepatitis B-immune donor.Gastroenterology 1993 Jun;104(6):1818-21
Chronic hepatitis B virus (HBV) infection is still a major cause of liver disease for which no definite therapy is available. We describe here a hepatitis B surface antigen (HBsAg) carrier patient with active viral replication (HBV DNA positive) who was treated for leukemia by bone marrow transplantation (BMT) from an HBV immune donor. Following BMT from the antibody to hepatitis B core antigen (anti-HBc) positive/anti-HBs positive bone marrow donor, immune reconstitution of the recipient's bone marrow resulted in clearance of the circulating HBsAg, as well as HBV DNA. The patient acquired immunity against HBV, which lasted for more than 8 months posttransplantation. Therefore, this report provides evidence that adoptive transfer of specific immunity against HBV through allogeneic BMT may lead to clearance of persistent HBV infection. Furthermore, the data support the hypothesis that the HBsAg carrier state is most probably the result of an inefficient immune response against HBV, implying that clearance of HBV may be facilitated by adoptive cellular immunotherapy.
采用天然HBV免疫的供体进行BMT可治愈慢性HBV感染受体的HBV感染，因此细胞过继免疫疗法是清除HBV感染有力手段
5）Shouval D, Adler R, Ilan Y. Adoptive transfer of immunity to hepatitis B virus in mice by bone marrow transplantation from immune donors.Hepatology 1993 Jun;17(6):955-9
Recipients of allogeneic bone marrow transplantation are immunosuppressed as a result of their primary disease and by myeloablative therapy. Such patients are dependent on multiple blood products and are at risk for hepatitis B virus infection. Active immunization against hepatitis B in the immediate pre- and post-transplant periods is ineffective, presumably because of decreased T cell-dependent B-cell responses. This study was designed to evaluate, in a mouse model system, the transfer of immunity against hepatitis B to bone marrow transplant recipients through immunization of bone marrow donors against hepatitis B before transplantation. Bone marrow donor BALB/c mice were immunized with a recombinant hepatitis B vaccine. Seroconversion to HBs antibody occurred within 4 wk of primary immunization, and antibody levels in treated donor mice rose above 300 mIU/ml after a single booster injection. Bone marrow recipient mice, conditioned by sublethal irradiation, were injected intravenously with bone marrow cells obtained from syngeneic HBs antibody-positive immune donors. Antibody was detected in 10% of bone marrow recipients within 30 days of transplantation and in 56% 1 mo after a booster injection that led to a secondary rise in HBs antibody. Adoptive transfer of immunity to hepatitis B also occurred after transplantation of T cell-depleted bone marrow cells from hepatitis B-immune donors, albeit at a lower HBs antibody level. These results indicate that immunity to hepatitis B can be transferred in mice by bone marrow transplantation from hepatitis B-immune donors to immunosuppressed recipients.(ABSTRACT TRUNCATED AT 250 WORDS)
采用HBV免疫的供体/小鼠进行BMT细胞过继免疫，可致受体的抗HBS产生增加，且去除T细胞亦有一定作用，说明DC/APC和T细胞均、有益于抗HBS抗体的产生，说明DC--TH1-BLC轴对于抗病毒免疫体液免疫产生很重要
6）Ilan Y, Nagler A, Adler R, Naparstek E, Or R, Slavin S, Brautbar C, Shouval D. Adoptive transfer of immunity to hepatitis B virus after T cell-depleted allogeneic bone marrow transplantation. Hepatology 1993 Aug;18(2):246-52
Recipients of allogeneic bone marrow transplantation are pancytopenic for several weeks and immunosuppressed for many months as a result of myeloablative therapy required to eliminate the basic disease and to prevent allograft rejection. After bone marrow transplantation, these patients remain profoundly immunosuppressed by the chemotherapy and immunotherapy used as prophylaxis against graft-vs.-host disease, treatment of established disease or both. These patients are usually dependent on multiple blood products and are therefore at risk for hepatitis B virus infection, which may run a fulminant course. Active immunization against hepatitis B virus in the immediate pre-bone marrow transplantation and post-bone marrow transplantation periods was found to be ineffective, probably because of the absence of T cell-dependent B-cell responses, which persists for approximately 1 yr after bone marrow transplantation. We studied adoptive transfer of immunity to hepatitis B virus through bone marrow transplantation in two populations of patients. The first group (A) consisted of 12 pairs of BMT donors and recipients, in which all bone marrow donors were positive for antibodies to HBc and HBs as a result of previously acquired hepatitis B virus infection and resolution; all recipients were negative to antibodies to HBc and HBs. The second group (B) consisted of eight pairs of donors and recipients in which all the donors were actively immunized against hepatitis B virus before bone marrow transplantation; all recipients were negative for all hepatitis B virus markers. All bone marrow transplantation recipients were monitored for antibodies to hepatitis B virus antigens.(ABSTRACT TRUNCATED AT 250 WORDS)
采用HBV免疫的供体/小鼠进行BMT细胞过继免疫，可致受体的抗HBS产生增加，且去除T细胞亦有一定作用，说明DC/APC和T细胞均、有益于抗HBS抗体的产生，说明DC--TH1-BLC轴对于抗病毒免疫体液免疫产生很重要
7）Ilan Y, Nagler A, Shouval D, Ackerstein A, Or R, Kapelushnik J, Adler R, Slavin S. Development of antibodies to hepatitis B virus surface antigen in bone marrow transplant recipient following treatment with peripheral blood lymphocytes from immunized donors.Clin Exp Immunol 1994 Aug;97(2):299-302
Bone marrow transplantation (BMT) recipients are immunosuppressed and are at risk for contracting severe infections. Recently, adoptive transfer of immunity against hepatitis B virus (HBV) was documented in BMT recipients receiving bone marrow from 'naturally' HBV-infected individuals who recovered spontaneously, or those transplanted with bone marrow cells obtained from actively immunized donors. Furthermore, reconstitution of the immune system in a BMT recipient who was a hepatitis surface antigen (HBsAg)+/HBV DNA+ carrier with HBV immune bone marrow cells led to clearance of the replicating virus, presumably through adoptive cell-mediated immunotherapy. We report three cases of induction of immunity to HBV by selective adoptive transfer by i.v. injection of peripheral blood lymphocytes (PBL) obtained from BMT donors who were actively immunized against HBV after harvesting of bone marrow. All three BMT recipients developed anti-HBs antibodies. In one BMT case in whom antibodies to HBsAg developed following adoptive transfer of immune PBL, a mild booster effect was documented in the BMT recipient upon immunization with a recombinant hepatitis B vaccine. The two remaining patients lost their antibodies to HBsAg in association with relapse of leukaemia. This immune manipulation may open the door to evaluation of adoptive transfer of immunity to HBV through selective transplantation of HBV immune lymphocytes in selected patients such as those with persistent HBV infection, as well as liver transplant recipients who require protection of the graft against HBV re-infection.
HBV感染受体选择性过继已采用HBV疫苗主动免疫的供者/供体的外周血淋巴细胞（CD4+？？？？）便可成功地治疗受体的HBV感染并产生抗HBV抗体，且因免疫不同功能状态而产生抗HBS抗体与否及消失与否，因此对受体的CD4+治疗或过继已采用HBV疫苗主动免疫的供者/供体的外周血淋巴细胞中CD4+可能是一法，而HBV疫苗尤常规疫苗似可作治疗性疫苗用？？？？
8）Shouval D, Ilan Y.Immunization against hepatitis B through adoptive transfer of immunity. Intervirology 1995;38(1-2):41-6
Clearance of hepatitis B virus (HBV) infection requires an effective T-cell-dependent humoral response that is often defective in HBV carriers and in immunosuppressed patients. We have shown in mice and humans that bone marrow (BM)-derived memory cells, capable of producing antibodies to the HBV envelope and nucleocapsid antigens, are transferable from BM donors (BMD) to their recipients. BMD BALB/c mice were immunized with recombinant HBV surface antigen (HBsAg), and BM from anti-HBs-positive donors was transplanted to irradiated recipient mice, who seroconverted to anti-HBs within 30 days of bone marrow transplantation (BMT), and responded to booster vaccination. In a similar manner, 19/26 human BM recipients, who received their HLA-matched BM from BMDs immunized once with HBsAg, seroconverted within several weeks after BMT. Antibodies to observHBsAg were alsoed in 3 recipients of peripheral blood lymphocytes (PBL) obtained from HLA-matched immunized human donors. Finally, clearance of HBsAg and HBV DNA was observed in an HBsAg carrier with leukemia who received BMT from his HLA-matched anti-HBc+/anti-HBs+ brother. These results indicate that adoptive transfer of immunity to HBV may be achieved through immunization of BM or PBL donors against HBV.
采用过继已采用HBV疫苗主动免疫的供者/供体的外周血淋巴细胞或者接受天然HBV免疫的供体进行BMT,均致HBV感染者的HBS AG清除和抗HBS抗体产生
9）Nagler A, Ilan Y, Adler R, Or R, Naparstek E, Shouval D, Slavin S. Successful immunization of autologous bone marrow transplantation recipients against hepatitis B virus by active vaccination.Bone Marrow Transplant 1995 Mar;15(3):475-8
Patients undergoing autologous bone marrow transplantation (BMT) are severely immunosuppressed. These patients are exposed to various infections agents due to delayed and efficient reconstitution of their immune system. Forty-eight patients with hemato-oncological malignancies were immunized against hepatitis B virus (HBV) following autologous BMT. Twenty one were vaccinated more than 10 days before BMT, 17 on days 1-9 before and 10 day after BMT. Thirty three patients (68.7%) seroconverted within 40 days after autologous BMT after receiving one dose of the vaccine before autologous BMT with a relatively low level of anti-HBs, whereas in 11 no anti-HBV antibodies could be detected. Nineteen patients remained seropositive but in 11 the seroconversion was only transient no correlation was found between permanent or transient seroconversion and basic disease, conditioning regimens, post-transplant therapy, immunotherapy and day of vaccination in relation to autologous and day of vaccination in relation to autologous BMT. Active HBV immunization of patients with malignancy undergoing autologous BMT is feasible and levels of antibodies, although low, are above the conventional protective titers. Therefore active immunization of some patients may reduce hepatitis-related complications in the setting of autologous BMT.
自体BMT前主动HBV免疫接种有效于产生抗HBS抗体
10）Nagler A, Ilan Y, Varadi G, Kapelushnik J, Or R. In vivo CAMPATH-1 followed by T cell-depleted bone marrow transplantation: a potential new mode of therapy for hepatitis-associated severe aplastic anemia (SAA). Bone Marrow Transplant 1996 Aug;18(2):475-8
Bone marrow transplantation (BMT) has been previously reported as a successful mode of treatment for hepatitis B and associated severe aplastic anemia (SAA). Non-A, non-B, non-C hepatitis is one of the causes of SAA. The etiology of SAA caused by non-A, non-B, non-C hepatitis is unknown. There is evidence that the immune response and, specifically, T cells and monocytes have a major role in both HCV- and HBV-induced liver damage. The liver damage caused by non-A, non-B, non-C hepatitis may be associated with similar mechanisms. We describe an 8-year-old girl who developed SAA post-non-A, non-B, non-C hepatitis infection. She was treated by in vivo CAMPATH-1G antibodies followed by T cell depleted HLA-matched BMT and cyclosporin A, resulting in gradual improvement and almost normalization of liver function. We suggest that treatment with CAMPATH-1G followed by T cell-depleted BMT and cyclosporin A could be a novel mode of therapy for viral non-A, non-B, non-C hepatitis-induced liver damage and associated SAA.
连最简单的非病原特异性BMT细胞过继免疫便可治NANBNC性肝炎呢
11）Lau GK, Lok AS, Liang RH, Lai CL, Chiu EK, Lau YL, Lam SK.Clearance of hepatitis B surface antigen after bone marrow transplantation: role of adoptive immunity transfer. Hepatology 1997 Jun;25(6):1497-501
Adoptive immunity transfer has been reported to be effective in clearing chronic hepatitis B virus (HBV) infection. Two hundred twenty-six patients who received allogeneic bone marrow transplantation (BMT) between May 1990 and September 1995 were screened for hepatitis B markers. Twenty-one patients were hepatitis B surface antigen (HBsAg) positive before BMT. The median follow-up period was 20 months (range, 2-59 months). Two of these patients had sustained clearance of HBV infection after transplantation. Both patients were hepatitis B e antigen (HBeAg)-negative, hepatitis B e antibody (anti-HBe)-positive, and serum HBV DNA-negative (by dot-blot hybridization) before BMT. Both had a flare in the serum alanine transaminase (ALT) level around the time of HBsAg clearance. Sustained clearance of HBsAg was observed in 2 of the 5 patients who received hepatitis B surface antibody (anti-HBs)-positive marrow but in none of the 16 patients who received anti-HBs-negative marrow (P < .05). One additional patient who received anti-HBs-positive marrow had transient HBsAg seroconversion. Among the 18 patients who remained persistently HBsAg-positive after BMT, 3 had HBeAg seroconversion and 3 had reversion to HBeAg positivity. In this study, we found a significant association between clearance of HBV infection and anti-HBs-positive bone marrow donors. Adoptive immunity transfer is effective in clearing HBV from patients with chronic HBV infection.
BMT中，HBV清除与 anti-HBs阳性BMT供体有关，因此采用天然HBV免疫的供体进行BMT通过过继免疫而治愈HBV感染
12）Ilan Y, Gabay E, Amit G, Feder R, Galun E, Adler R, Shouval D. Suppression of human hepatoma in mice through adoptive transfer of immunity to the hepatitis B surface antigen. J Hepatol 1997 Jul;27(1):170-5
BACKGROUND/AIMS: Adoptive transfer of immunity against hepatitis B surface antigen (HBsAg) has previously been shown to occur in mice and humans through transplantation of bone marrow cells from donors immunized against HBsAg (anti-HBs) to non-immune recipients. In the present study we evaluated the effect of adoptive transfer of immunity to HBsAg on the growth of HbsAg-secreting hepatocellular carcinoma (HCC) xenografts in athymic mice. METHODS: Immunocompetent mice were immunized with recombinant HBsAg. Bone marrow cells from anti-HBs+ mice were injected intravenously to irradiated athymic Balb/c mice which had been previously transplanted subcutaneously with Hep3B human hepatoma cells. Treatment groups included mice receiving bone marrow transplantation from HBV-immunized (anti-HBs positive) and non-immunized (anti-HBs negative) donors. RESULTS: At 9 weeks post bone marrow transplantation, tumor volume and serum alpha-fetoprotein levels in athymic mice receiving HBV-immune bone marrow cells were 11.5 mm3 and 363 ng/ml, respectively, as compared to 1579 mm3 and 19,000 ng/ml, in recipients of non-immune bone marrow transplantation (p<0.005). T-cell depletion of antiHBs+ immune bone marrow prior to transplantation decreased the anti-tumor effect but did not abolish it. A mild nonspecific, bone marrow-derived, graft versus tumor effect was observed in mice transplanted with human hepatoma cells that do not express HBsAg. CONCLUSIONS: Adoptive transfer of immunity to HBV facilitates suppression of experimental human HCC expressing HBsAg. This effect is the result of a combination of specific anti-viral surface antigen effect and a nonspecific graft versus tumor effect.
采用HBV免疫的供体进行BMT通过过继免疫而控制HBV感染性肝癌呢
13）Lau GK, Liang R, Lee CK, Yuen ST, Hou J, Lim WL, Williams R. Clearance of persistent hepatitis B virus infection in Chinese bone marrow transplant recipients whose donors were anti-hepatitis B core- and anti-hepatitis B surface antibody-positive. J Infect Dis 1998 Dec;178(6):1585-91
Thirteen hepatitis B surface antigen-positive Chinese patients who received hepatitis B surface antibody-positive marrow (hepatitis B core antibody-positive or -negative: 6 and 7, respectively) via allogeneic bone marrow transplantation (BMT) were studied. After BMT, 4 recipients had serologic clearance of hepatitis B surface antigen from hepatitis B core antibody-positive marrow, but none of the recipients of hepatitis B core antibody-negative marrow had serologic clearance (P=.02). There was no significant difference in the donors' hepatitis B surface antibody titer before BMT for patients with or without serologic clearance of hepatitis B surface antigen (2255.2+/-4244.0 vs. 854.2+/-2306.7 mIU/mL; P=not significant). Adoptive immunity clearance of hepatitis B surface antigen was favored by hepatitis B core antibody positive-donor marrow and was not related to donor pre-BMT hepatitis B surface antibody titer.
采用天然HBV免疫的供体进行BMT通过过继免疫而治愈HBV感染，而且发现HBV感染治治愈与供体的抗HBC抗体有关而与抗HBS抗体无关。说明HBC AG的免疫反应有利于治疗HBV感染而HBS AG的免疫反应仅有利于防止HBV再感染
14）Lau GK, Yuen ST, Au WY, Wu PC, Liang R. Histological changes during clearance of chronic hepatitis B virus infection by adoptive immunity transfer. J Gastroenterol Hepatol 1999 Mar;14(3):262-8
BACKGROUND: Serological clearance of hepatitis B surface antigen (HBsAg) has been described after reception of hepatitis B surface antibody positive marrow, via allogeneic bone marrow transplantation (BMT). Histological changes during the clearance of HBsAg are unknown. METHODS AND RESULTS: We described two chronic hepatitis B carriers (both hepatitis B e antigen negative), who cleared HBsAg after allogeneic bone marrow transplantation. Both received hepatitis B surface and core antibody positive human leucocyte antigen identical donors' marrow and had serological clearance of HBsAg 15 and 7 weeks after allogeneic BMT, respectively. Both events were preceded by hepatic flare. Both patients were also treated with famciclovir for the prevention of hepatitis B reactivation after BMT. Histological examination during the flare showed only mild necroinflammatory activity with multiple foci of confluent necrosis, associated with moderate lymphocytic infiltration. The majority of these lymphocytes were cluster of differentiation (CD) 8 positive. Using immunohistochemistry, there was no detectable hepatic expression of hepatitis B core antigen. However, HBsAg was positive, mainly in the area of confluent necrosis. Using in situ hybridization, hepatitis B virus (HBV) DNA was detected in the nucleus of 5% of hepatocytes, but not in the cytoplasm. CONCLUSIONS: At their last follow up, 22 and 16 months after BMT, the serum of both patients remained HBsAg negative, hepatitis B surface antibody positive and HBV-DNA negative by branched DNA assay.
采用天然HBV免疫的供体进行BMT通过过继免疫而治愈HBV感染，但血清HBV指标转阴而肝细胞核内仍有极微量的HBVDNA存在，此少量HBV DNA只有在机体免疫功能明显下降时才又发病，这又解释了为什么抗HBS抗体阳性血液病/白血病病人进行BMT后因防排斥反应而使用免疫抑制剂后致体内仅存的极微量的HBV病毒复燃而大量复制，故诱发肝炎发作甚至重症肝炎
15）Ilan Y, Nagler A, Zeira E, Adler R, Slavin S, Shouval D.Maintenance of immune memory to the hepatitis B envelope protein following adoptive transfer of immunity in bone marrow transplant recipients. Bone Marrow Transplant 2000 Sep;26(6):633-8
Adoptive transfer of immunity against hepatitis B surface antigen (HBsAg) has been documented in mice and humans. In the present study, we report long-term follow-up of antibodies to HBsAg in humans who received allogeneic bone marrow transplantation (BMT) from donors immunized with HBsAg. BM donors were immunized with recombinant HBsAg. BM or PB cells were transplanted to HLA matched recipients. Recipients were followed for anti-HBs seroconversion. Control groups included non-immunized or rHBsAg immunized healthy adults as well as individuals that had had hepatitis B and recovered spontaneously. PBLs were stimulated in vitro with rHBsAg and stimulation was expressed as stimulation index. Adoptive transfer of immunity to HBsAg was initially documented in 12 recipients of BM from anti-HBc+/anti-HBs+ donors. An almost 4 year follow-up showed detectable protective anti-HBs levels (>10 mIU/ml) in 50% of patients. Immunity to HBV was also documented in 22/35 BMT recipients (62%), who received their bone marrow from actively immunized donors. In 7/9 of these BMT recipients, anti-HBs antibodies levels were documented 25 months following BMT. In 6/8 (75%) of patients who received only PBLs from HBV immune donors, adoptive transfer of immunity to HBV, and seroconversion to HBsAg+, were documented within 2 months of i.v. injection. Evidence for specific cellular immune response with increased SIs was documented for healthy vaccinees, and BMT recipients, and in none of the healthy non-vaccinated controls. These results suggest that adoptive transfer of immunity to HBV is a useful method for providing long-lasting protection for BM recipients.
采用过继已采用HBV疫苗主动免疫的供者/供体的外周血淋巴细胞或者接受天然HBV免疫的供体进行BMT,均致受体抗HBS抗体产生
15） Lau GK, Suri D, Liang R, Rigopoulou EI, Thomas MG, Mullerova I, Nanji A, Yuen ST, Williams R, Naoumov NV.Resolution of chronic hepatitis B and anti-HBs seroconversion in humans by adoptive transfer of immunity to hepatitis B core antigen.Gastroenterology 2002 Mar;122(3):614-24
BACKGROUND & AIMS: Impaired T-cell reactivity is believed to be the dominant cause of chronic hepatitis B virus (HBV) infection. We characterized HBV-specific T-cell responses in chronic hepatitis B surface antigen carriers who received bone marrow from HLA-identical donors with natural immunity to HBV and seroconverted to antibody to hepatitis B surface antigen. METHODS: T-cell reactivity to HBV antigens and peptides was assessed in a proliferation assay, the frequency of HBV core- and surface-specific T cells was quantified directly by ELISPOT assays, and T-cell subsets were analyzed by flow cytometry. RESULTS: CD4+ T-cell reactivity to HBV core was common in bone marrow donors and the corresponding recipients after hepatitis B surface antigen clearance, whereas none reacted to surface, pre-S1, or pre-S2 antigens. Furthermore, CD4+ T cells from donor/recipient pairs recognized similar epitopes on hepatitis B core antigen; using polymerase chain reaction for the Y chromosome, the recipients' CD4+ T lymphocytes were confirmed to be of donor origin. The frequency of core-specific CD4+ and CD8+ T cells was several-fold higher than those specific for surface antigen. CONCLUSIONS: This study provides the first evidence in humans that transfer of hepatitis B core antigen-reactive T cells is associated with resolution of chronic HBV infection. Therapeutic immunization with HBV core gene or protein deserves further investigation in patients with chronic hepatitis B.
接受天然HBV免疫的供体进行BMT致HBV感染者的HBS AG清除，其HBV清除作用与HBC AG特异性TH/CD4T细胞从天然HBV免疫的供体过继给HBV感染的受体有密切关系，即天然HBV免疫的供体的HBC AG特异性TH/CD4T细胞在受体内长期存在于受者体内并发挥其抗HBV免疫的免疫调控作用