X连锁严重联合免疫缺陷(X-linked severe combined Immunodeficiency,X-SCID)是由编码普通γ链(IL2RG)的基因突变引起的一种罕见的危及生命的疾病。目前国内有散发的病例报道,本文通过1例IL2RG基因新突变致X-连锁联合免疫缺陷的报道,希...X连锁严重联合免疫缺陷(X-linked severe combined Immunodeficiency,X-SCID)是由编码普通γ链(IL2RG)的基因突变引起的一种罕见的危及生命的疾病。目前国内有散发的病例报道,本文通过1例IL2RG基因新突变致X-连锁联合免疫缺陷的报道,希望增加对非典型X-SCID的认识,有助于早期诊断该类疾病。展开更多
X-linked severe combined immunodeficiency disease(X-SCID)is a rare inheriteddisease caused by mutations in the interleukin 2 receptor subunit gamma gene(IL2RG),whichencodes the common g chain protein,a subunit of the ...X-linked severe combined immunodeficiency disease(X-SCID)is a rare inheriteddisease caused by mutations in the interleukin 2 receptor subunit gamma gene(IL2RG),whichencodes the common g chain protein,a subunit of the receptor for lymphocytes.X-SCID ischaracterized by profound defects in T-cell,B-cell,and natural killer cell function.Here,we report a Chinese cohort of nine X-SCID patients with six novel IL2RG mutations.Amongthose,the two adolescent patients with an atypical immunotype were confirmed by furtheranalyzing IL-2-JAK-STAT5 signaling,T cell proliferation,and T cell receptor excision circles(Trecs).Interestingly,Bacillus Calmette-Guerin(BCG)disease occurred commonly in thiscohort.Although allogeneic hematopoietic stem-cell transplantation is curative for the disease,it is not available to all patients due to the lack of suitable matched donors.Autologousgene therapy using a self-inactivating lentiviral vector(SIN-LV)technology has provided analternative therapy for such mono-genetic diseases.Here,we performed the pre-clinicalstudies to assess our SIN-LV carrying IL2RG on human ED7R cells deficient in IL2RG andCD34^(+)stem cells derived from the bone marrow of a healthy donor and a patient with X-SCID.This work is done complied with the established“Good Manufacturing Practice”(GMP)used inthe clinical trials.In addition,a safety study is performed using the transduced CD34^(+)cells implanted into the axilla of nude mice in vivo.Overall,our studies have demonstrated the efficiency and safety of SIN-IL2RG-LV,which paves the way for conducting X-SCID gene therapyclinical trials in China in the near future.展开更多
Adult T-cell leukemia( ATL) is a mature T-cell malignancy caused by human T-cell leukemia virus type I infection, and 10%-25% of patients show central nervous system( CNS) involvement. CNS involvement significantly re...Adult T-cell leukemia( ATL) is a mature T-cell malignancy caused by human T-cell leukemia virus type I infection, and 10%-25% of patients show central nervous system( CNS) involvement. CNS involvement significantly reduces survival and there are no effective treatments for CNS involvement. Therefore, an appropriate animal model is required to evaluate the inhibitory effects of novel drugs on the progression of ATL with CNS involvement. Here, we established a mouse model of ATL with CNS involvement using NOD.Cg-Prkdc~ (scid) Il2 rg ^(tm1Wjl)/SzJ mice inoculated with ATL cells intramuscularly in the postauricular region, and these mice showed paraparesis. Of the 10 mice inoculated with ATL cells intramuscularly(I.M.) at 5 weeks of age, 8(80%) showed paraparesis, whereas none of the 10 mice inoculated with ATL cells subcutaneously(S.C.) showed paraparesis. In the I.M. group, PCR detected HTLV-1-specific genes in the thoracic and lumbar vertebrae; however, in the S.C. group, the vertebrae were negative for HTLV-1 genes. Histological analysis revealed a particularly high incidence of tumors, characterized by accumulation of the injected cells, in the thoracic vertebrae of mice in the I.M. group. Tumor cell infiltration was relatively high in the bone marrow. Spinal cord compression caused by invasion of the tumor mass outside the pia mater was observed in the thoracic vertebrae of the spinal cord. In conclusion, we have reported a mouse model of tumor growth with paraparesis that may be used to assess novel therapeutic agents for ATL with CNS involvement.展开更多
报告1例新生儿期确诊X-连锁重症联合免疫缺陷病(X-linked severe combined immunodeficiency,X-SCID)的患儿,以淋巴细胞计数持续减低、反复感染为主要表现,淋巴细胞亚群示T细胞、自然杀伤性细胞减少,胸部X线片未见胸腺影,家系全外显子...报告1例新生儿期确诊X-连锁重症联合免疫缺陷病(X-linked severe combined immunodeficiency,X-SCID)的患儿,以淋巴细胞计数持续减低、反复感染为主要表现,淋巴细胞亚群示T细胞、自然杀伤性细胞减少,胸部X线片未见胸腺影,家系全外显子组测序确诊为IL2RG基因变异所致的X-SCID。生后5月龄行骨髓移植治疗,现11月龄,淋巴细胞计数正常,未再发生感染,预后良好。展开更多
文摘X连锁严重联合免疫缺陷(X-linked severe combined Immunodeficiency,X-SCID)是由编码普通γ链(IL2RG)的基因突变引起的一种罕见的危及生命的疾病。目前国内有散发的病例报道,本文通过1例IL2RG基因新突变致X-连锁联合免疫缺陷的报道,希望增加对非典型X-SCID的认识,有助于早期诊断该类疾病。
基金supported by the National Natural Science Foundation of China(No.82070135)the National Key R&D Program of China(No.2021YFC2700804)the CQMU Program for Youth Innovation in Future Medicine(China)(No.W0100).
文摘X-linked severe combined immunodeficiency disease(X-SCID)is a rare inheriteddisease caused by mutations in the interleukin 2 receptor subunit gamma gene(IL2RG),whichencodes the common g chain protein,a subunit of the receptor for lymphocytes.X-SCID ischaracterized by profound defects in T-cell,B-cell,and natural killer cell function.Here,we report a Chinese cohort of nine X-SCID patients with six novel IL2RG mutations.Amongthose,the two adolescent patients with an atypical immunotype were confirmed by furtheranalyzing IL-2-JAK-STAT5 signaling,T cell proliferation,and T cell receptor excision circles(Trecs).Interestingly,Bacillus Calmette-Guerin(BCG)disease occurred commonly in thiscohort.Although allogeneic hematopoietic stem-cell transplantation is curative for the disease,it is not available to all patients due to the lack of suitable matched donors.Autologousgene therapy using a self-inactivating lentiviral vector(SIN-LV)technology has provided analternative therapy for such mono-genetic diseases.Here,we performed the pre-clinicalstudies to assess our SIN-LV carrying IL2RG on human ED7R cells deficient in IL2RG andCD34^(+)stem cells derived from the bone marrow of a healthy donor and a patient with X-SCID.This work is done complied with the established“Good Manufacturing Practice”(GMP)used inthe clinical trials.In addition,a safety study is performed using the transduced CD34^(+)cells implanted into the axilla of nude mice in vivo.Overall,our studies have demonstrated the efficiency and safety of SIN-IL2RG-LV,which paves the way for conducting X-SCID gene therapyclinical trials in China in the near future.
基金Japan Leukemia Research FundGrant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science,Grant/Award Number:No.24500493
文摘Adult T-cell leukemia( ATL) is a mature T-cell malignancy caused by human T-cell leukemia virus type I infection, and 10%-25% of patients show central nervous system( CNS) involvement. CNS involvement significantly reduces survival and there are no effective treatments for CNS involvement. Therefore, an appropriate animal model is required to evaluate the inhibitory effects of novel drugs on the progression of ATL with CNS involvement. Here, we established a mouse model of ATL with CNS involvement using NOD.Cg-Prkdc~ (scid) Il2 rg ^(tm1Wjl)/SzJ mice inoculated with ATL cells intramuscularly in the postauricular region, and these mice showed paraparesis. Of the 10 mice inoculated with ATL cells intramuscularly(I.M.) at 5 weeks of age, 8(80%) showed paraparesis, whereas none of the 10 mice inoculated with ATL cells subcutaneously(S.C.) showed paraparesis. In the I.M. group, PCR detected HTLV-1-specific genes in the thoracic and lumbar vertebrae; however, in the S.C. group, the vertebrae were negative for HTLV-1 genes. Histological analysis revealed a particularly high incidence of tumors, characterized by accumulation of the injected cells, in the thoracic vertebrae of mice in the I.M. group. Tumor cell infiltration was relatively high in the bone marrow. Spinal cord compression caused by invasion of the tumor mass outside the pia mater was observed in the thoracic vertebrae of the spinal cord. In conclusion, we have reported a mouse model of tumor growth with paraparesis that may be used to assess novel therapeutic agents for ATL with CNS involvement.
文摘报告1例新生儿期确诊X-连锁重症联合免疫缺陷病(X-linked severe combined immunodeficiency,X-SCID)的患儿,以淋巴细胞计数持续减低、反复感染为主要表现,淋巴细胞亚群示T细胞、自然杀伤性细胞减少,胸部X线片未见胸腺影,家系全外显子组测序确诊为IL2RG基因变异所致的X-SCID。生后5月龄行骨髓移植治疗,现11月龄,淋巴细胞计数正常,未再发生感染,预后良好。
