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              1. 主页 > 乙肝新闻 > 新药研制 >

              骨髓移植或治疗性复合疫苗或能根治乙肝?

                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。

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