公开(公告)号：US5637454A

公开(公告)日：1997-06-10

申请号：US335198

申请日：1994-11-07

申请人： John B. Harley

发明人： John B. Harley

IPC分类号： A61K38/00 ,  A61K39/00 ,  C07K14/145 ,  C07K14/47 ,  G01N33/564 ,  G01N33/569 ,  G01N33/68

CPC分类号： C07K14/005 ,  C07K14/4713 ,  G01N33/564 ,  G01N33/56983 ,  G01N33/6878 ,  A01K2267/0325 ,  A61K38/00 ,  A61K39/00 ,  C12N2760/20222 ,  G01N2800/104 ,  G01N2800/24

摘要： A specific method has been developed to identify the etiologic or immunogenic agent responsible for the production of autoantibodies characteristic of a particular disorder or immune response. The antigen is first isolated, then divided into overlapping short amino acid sequences. The sequences having the greatest reactivity with the autoantibodies are identified and compared with all known amino acids sequences using the available computer data bases. The protein having the maximum number of sequences homologous to the sequences of greatest reactivity with the autoantibodies is the likeliest candidate for the etiological agent. Applying this method, it has been determined that the etiological agent for the production of anti-Ro/SSA autoantibodies characteristic of numerous autoimmune diseases such as SLE appears to be a virus highly homologous to the Indiana strain of the vesicular stomatitis virus. Once the etiologic agent and antigenic sequences are known, it is possible to design assays and reagents for the diagnosis and treatment of patients having either the etiological agent and/or autoantibodies. An animal model has been developed for studying the mechanisms of, and screening compounds for the treatment or prevention of, the expression of these autoantibodies.

摘要翻译： 已经开发了一种具体方法来鉴定负责产生特异性病症或免疫应答特征的自身抗体的病原体或免疫原性试剂。 首先分离抗原，然后分成重叠的短氨基酸序列。 鉴定与自身抗体具有最大反应性的序列，并使用可用的计算机数据库与所有已知的氨基酸序列进行比较。 具有与与自身抗体最大反应性序列同源的序列的最大数目的蛋白质是病原体的最可能的候选物。 应用这种方法，已经确定用于产生许多自身免疫性疾病如SLE特征的抗Ro / SSA自身抗体的病原体似乎是与水泡性口炎病毒的印第安纳菌株高度同源的病毒。 一旦病原体和抗原序列是已知的，可以设计用于诊断和治疗患有病原体和/或自身抗体的患者的测定和试剂。 已经开发了一种动物模型，用于研究这些自身抗体表达的机制和筛选化合物用于治疗或预防这些自身抗体的表达。

公开(公告)号：US07888458B1

公开(公告)日：2011-02-15

申请号：US08781296

申请日：1997-01-13

申请人： John B. Harley ,  Judith A. James

发明人： John B. Harley ,  Judith A. James

IPC分类号： A61K38/00 ,  A61K39/00 ,  A61K39/395 ,  G01N33/53

CPC分类号： C07K14/005 ,  A61K39/00 ,  C12N2710/16222 ,  C12N2710/16622 ,  G01N2800/24 ,  Y02A50/386 ,  Y02A50/414

摘要： Data consistent with autoimmune disease being caused by Epstein-Barr virus are shown. Based on this evidence, an effective vaccine would prevent the autoimmune disease in those vaccinated, modified or administered so that the vaccine is not itself capable of inducing autoimmune disease. In the case of anti-Sm, structures to be avoided in an Epstein-Barr virus-derived vaccine have been identified. Differences have been identified in the immune responses to Epstein-Barr infection between individuals who develop a specific autoimmune disease and those who do not. These differences are used to distinguish those who are at greater risk for developing specific autoimmune diseases from those who are a lesser risk. Assuming Epstein-Barr virus causes autoimmune disease and that Epstein-Barr virus remains latent in the patient for life, reactivation of the virus from the latent state is important in generating or maintaining the autoimmune response that culminates in autoimmune disease. Cells infected with latent virus may also encourage autoimmunity. Based on the understanding that reactivation or latency are important to produce or sustain autoimmunity, then therapies directed against Epstein-Barr virus will also be effective therapies for the autoimmune manifestations of disease for which Epstein-Barr virus is responsible.

摘要翻译： 显示与Epstein-Barr病毒引起的与自身免疫性疾病相一致的数据。 基于这一证据，有效的疫苗将防止那些接种，修饰或施用的自身免疫疾病，使得疫苗本身不能诱导自身免疫性疾病。 在抗Sm的情况下，已经鉴定了在爱泼斯坦 - 巴尔病毒来源的疫苗中避免的结构。 在发展特异性自身免疫性疾病的个体与不发生特异性自身免疫性疾病的个体之间的爱泼斯坦 - 巴尔病毒感染的免疫应答中已经鉴定出差异。 这些差异用于区分发展特定自身免疫性疾病风险较高的人群与风险较小者。 假设爱泼斯坦 - 巴尔病毒导致自身免疫性疾病，并且爱泼斯坦 - 巴尔病毒在患者身上保持潜伏，病毒从潜在状态的再激活对于产生或维持自身免疫应答至关重要，其最终导致自身免疫性疾病。 感染潜伏病毒的细胞也可能会鼓励自身免疫。 基于认识到再激活或延迟对于产生或维持自身免疫是重要的，那么针对爱泼斯坦 - 巴尔病毒的疗法也将成为爱泼斯坦 - 巴尔病毒负责的疾病的自身免疫表现的有效疗法。

公开(公告)号：US07078173B2

公开(公告)日：2006-07-18

申请号：US10646132

申请日：2003-08-22

申请人： John B. Harley ,  Judith A. James ,  Kenneth M. Kaufman

发明人： John B. Harley ,  Judith A. James ,  Kenneth M. Kaufman

IPC分类号： C12Q1/70

CPC分类号： C07K14/005 ,  A61K39/00 ,  A61K39/12 ,  A61K39/245 ,  A61K2039/545 ,  A61K2039/55566 ,  C07K16/085 ,  C12N2710/16222 ,  C12N2710/16234 ,  Y02A50/386 ,  Y02A50/414

摘要： Compositions that bind viral proteins that are specifically expressed during the latent stage of the viral life cycle are disclosed. These compositions bind the latent viral proteins while the viral proteins are expressed in their cellular host, and provide a means for targeting cells that harbor latent virus. In a preferred embodiment the compositions are antibodies which bind the extracellular region of the latent viral protein, most preferably LMP-2A, an EBV latent protein, which are conjugated to a diagnostic or cytotoxic agent or immobilized to a solid support for removal of the infected cells. These antibodies are capable of distinguishing cells expressing EBV DNA from cells which are not expressing EBV DNA. Compositions that can be used to elicit production of these antibodies, or as a vaccine, are also disclosed. Methods for generating diagnostic or cytotoxic reagents and vaccines based on the viral epitopes that identify cells harboring latent virus are also disclosed. The antibody conjugates can be used in diagnostic assays to identify cells expressing latent viral protein and people who are harboring latent viral particles. The antibody conjugates can also be used to remove the infected cells or to kill the infected the cells. Alternatively, or in addition, the viral proteins or portions thereof can be used as a vaccine to induce an immune reaction by the host to kill the infected cells. These methods can be used to detect or treat patients harboring latent viruses like EBV and who are at risk of developing a disease such as an autoimmune disease like systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA).

公开(公告)号：US06641813B1

公开(公告)日：2003-11-04

申请号：US08475955

申请日：1995-06-07

申请人： John B. Harley

发明人： John B. Harley

IPC分类号： A61K3900

CPC分类号： C07K14/005 ,  A01K2267/0325 ,  A61K38/00 ,  A61K39/00 ,  C07K14/4713 ,  C12N2760/20222 ,  G01N33/564 ,  G01N33/56983 ,  G01N33/6878 ,  G01N2800/104 ,  G01N2800/24 ,  Y02A50/403

摘要： A number of octapeptides were generated from the sequences encoding the 60 kDa Ro/SSA peptide, the La/SSB autoantigen, the 70 kD nuclear ribonucleoprotein (nRNP), and the Sm B/B′ polypeptide, which represent linear epitopes for autoantibodies present in the sera of SLE and SS patients. These peptides are useful in solid phase assays for patients characterized by the presence of these autoantibodies, and can be used to categorize patients as to the likelihood of developing certain conditions associated with SLE. The peptides are also potentially useful in treatment of these patients using immobilized peptide to remove autoantibody and to block binding of the autoantibodies with patient molecules reactive with the autoantibodies.

摘要翻译： 从编码60kDa Ro / SSA肽，La / SSB自身抗原，70kD核核糖核蛋白（nRNP）和Sm B / B'多肽的序列产生许多八肽，其代表存在于自身抗体中的自身抗体的线性表位 SLE和SS患者的血清。 这些肽可用于以这些自身抗体存在为特征的患者的固相测定中，并且可用于将患者分类与发展与SLE相关的某些病症的可能性。 这些肽也可用于治疗这些患者，使用固定肽去除自身抗体并阻断自身抗体与与自身抗体反应的患者分子的结合。

公开(公告)号：US4784942A

公开(公告)日：1988-11-15

申请号：US670000

申请日：1984-11-05

申请人： John B. Harley

发明人： John B. Harley

IPC分类号： G01N33/564 ,  G01N33/68 ,  G01N33/577

CPC分类号： G01N33/6875 ,  G01N33/564 ,  G01N2800/104 ,  G01N2800/24 ,  Y10S435/805 ,  Y10S435/81 ,  Y10S435/975 ,  Y10S436/811 ,  Y10S530/808 ,  Y10S530/809 ,  Y10S530/866 ,  Y10S530/868

摘要： Monoclonal antibodies against autoimmune RNA proteins such as La/SSB, Ro/SSA, nNP, and Sm. These monoclonal antibodies which are produced by a continuous hybridoma cell line, may be used in methods for detecting the presence of selected autoimmune RNA proteins and antibodies against such proteins in biological samples, and may be incorporated into diagnostic test kits for this purpose. The monoclonal antibodies may be applied in methods for screening subjects for systemic lupus erythematosus, subacute cutaneous erythematosus, neonatal lupus, Sjogren's syndrome, complete congential heart block, and other disorders which involve the presence of antibodies against autoimmune RNA proteins.

摘要翻译： 抗自身免疫性RNA蛋白如La / SSB，Ro / SSA，nNP和Sm的单克隆抗体。 通过连续杂交瘤细胞系产生的这些单克隆抗体可用于检测生物样品中选择的自身免疫RNA蛋白和抗体对这种蛋白质的抗体的存在的方法，并且可以并入诊断测试试剂盒中用于此目的。 单克隆抗体可以用于筛选系统性红斑狼疮，亚急性皮肤红斑狼疮，新生儿狼疮，Sjögren综合征，完全先天性心脏阻塞的受试者和涉及针对自身免疫RNA蛋白的抗体存在的其它病症的方法。

公开(公告)号：US07410642B2

公开(公告)日：2008-08-12

申请号：US11405355

申请日：2006-04-17

申请人： John B. Harley ,  Judith Ann James ,  Kenneth M. Kaufman

发明人： John B. Harley ,  Judith Ann James ,  Kenneth M. Kaufman

IPC分类号： A61K39/12

CPC分类号： C07K14/005 ,  A61K39/00 ,  A61K39/12 ,  A61K39/245 ,  A61K2039/545 ,  A61K2039/55566 ,  C07K16/085 ,  C12N2710/16222 ,  C12N2710/16234 ,  Y02A50/386 ,  Y02A50/414

摘要： Compositions that bind viral proteins that are specifically expressed during the latent stage of the viral life cycle are disclosed. These compositions bind the latent viral proteins while the viral proteins are expressed in their cellular host, and provide a means for targeting cells that harbor latent virus. In a preferred embodiment the compositions are antibodies which bind the extracellular region of the latent viral protein, most preferably LMP-2A, an EBV latent protein, which are conjugated to a diagnostic or cytotoxic agent or immobilized to a solid support for removal of the infected cells. These antibodies are capable of distinguishing cells expressing EBV DNA from cells which are not expressing EBV DNA. Compositions that can be used to elicit production of these antibodies, or as a vaccine, are also disclosed. Methods for generating diagnostic or cytotoxic reagents and vaccines based on the viral epitopes that identify cells harboring latent virus are also disclosed. The antibody conjugates can be used in diagnostic assays to identify cells expressing latent viral protein and people who are harboring latent viral particles. The antibody conjugates can also be used to remove the infected cells or to kill the infected the cells. Alternatively, or in addition, the viral proteins or portions thereof can be used as a vaccine to induce an immune reaction by the host to kill the infected cells. These methods can be used to detect or treat patients harboring latent viruses like EBV and who are at risk of developing a disease such as an autoimmune disease like systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA).

摘要翻译： 公开了结合在病毒生命周期的潜在阶段中特异性表达的病毒蛋白质的组合物。 这些组合物结合潜在的病毒蛋白质，同时病毒蛋白质在其细胞宿主中表达，并提供靶向隐藏潜伏病毒的细胞的手段。 在优选的实施方案中，组合物是结合潜伏病毒蛋白质的细胞外区域，最优选LMP-2A，EBV潜伏蛋白的抗体，其与诊断性或细胞毒性剂缀合或固定在固体支持物上以去除感染的 细胞。 这些抗体能够区分表达EBV DNA的细胞与不表达EBV DNA的细胞。 还可以公开可用于引发这些抗体或疫苗生产的组合物。 还公开了用于产生诊断或细胞毒素试剂和基于鉴定携带潜伏病毒的细胞的病毒表位的疫苗的方法。 抗体缀合物可用于诊断测定以鉴定表达潜伏性病毒蛋白的细胞和携带潜伏病毒颗粒的人。 抗体缀合物也可用于去除被感染的细胞或杀死被感染的细胞。 或者或另外，病毒蛋白质或其部分可以用作疫苗以诱导宿主杀死受感染细胞的免疫反应。 这些方法可用于检测或治疗患有EBV等潜伏病毒的患者，以及患有诸如系统性红斑狼疮（SLE）和类风湿性关节炎（RA）等自身免疫性疾病的疾病的风险。

公开(公告)号：US07273613B1

公开(公告)日：2007-09-25

申请号：US09500904

申请日：2000-02-09

申请人： John B. Harley ,  Judith A. James ,  Kenneth M. Kaufman

发明人： John B. Harley ,  Judith A. James ,  Kenneth M. Kaufman

IPC分类号： C07K5/00 ,  A61K39/00 ,  C12Q1/70

CPC分类号： A61K39/245 ,  A61K39/00 ,  A61K39/12 ,  A61K2039/57 ,  C07K14/005 ,  C12N2710/16222 ,  C12N2710/16234 ,  Y02A50/386 ,  Y02A50/414 ,  Y10S435/975

摘要： Data consistent with autoimmune disease being caused by Epstein-Barr virus are shown. Based on this evidence, an effective vaccine would prevent the autoimmune disease in those vaccinated, modified or administered so that the vaccine is not itself capable of inducing autoimmune disease. In the case of anti-Sm, structures to be avoided in an Epstein-Barr virus-derived vaccine have been identified. Differences have been identified in the immune responses to Epstein-Barr infection between individuals who develop a specific autoimmune disease and those who do not. These differences are used to distinguish those who are at greater risk for developing specific autoimmune diseases from those who are a lesser risk. Assuming Epstein-Barr virus causes autoimmune disease and that Epstein-Barr virus remains latent in the patient for life, reactivation of the virus from the latent state is important in generating or maintaining the autoimmune response that culminates in autoimmune disease. Cells infected with latent virus may also encourage autoimmunity. Based on the understanding that reactivation or latency are important to produce or sustain autoimmunity, then therapies directed against Epstein-Barr virus will also be effective therapies for the autoimmune manifestations of disease for which Epstein-Barr virus is responsible.

摘要翻译： 显示与Epstein-Barr病毒引起的与自身免疫性疾病相一致的数据。 基于这一证据，有效的疫苗将防止那些接种，修饰或施用的自身免疫疾病，使得疫苗本身不能诱导自身免疫性疾病。 在抗Sm的情况下，已经鉴定了在爱泼斯坦 - 巴尔病毒来源的疫苗中避免的结构。 在发展特异性自身免疫性疾病的个体与不发生特异性自身免疫性疾病的个体之间的爱泼斯坦 - 巴尔病毒感染的免疫应答中已经鉴定出差异。 这些差异用于区分发展特定自身免疫性疾病风险较高的人群与风险较小的人群。 假设爱泼斯坦 - 巴尔病毒导致自身免疫性疾病，并且爱泼斯坦 - 巴尔病毒在患者身上保持潜伏，病毒从潜在状态的再激活对于产生或维持自身免疫应答至关重要，其最终导致自身免疫性疾病。 感染潜伏病毒的细胞也可能会鼓励自身免疫。 基于认识到再激活或延迟对于产生或维持自身免疫是重要的，那么针对爱泼斯坦 - 巴尔病毒的疗法也将成为爱泼斯坦 - 巴尔病毒负责的疾病的自身免疫表现的有效疗法。

公开(公告)号：US20090246768A1

公开(公告)日：2009-10-01

申请号：US12228085

申请日：2009-02-12

申请人： Amr H. Sawalha ,  John B. Harley

发明人： Amr H. Sawalha ,  John B. Harley

IPC分类号： C12Q1/68 ,  G01N33/566

CPC分类号： C12Q1/6876 ,  C12Q2600/156 ,  G01N33/564

摘要： The present invention provides methods for the prediction and diagnosis of autoimmune diseases, including Systemic Lupus Erythematosus, by identifying polymorphisms in the gene for MECP2.

摘要翻译： 本发明提供了通过鉴定MECP2基因多态性来预测和诊断包括系统性红斑狼疮的自身免疫性疾病的方法。

公开(公告)号：US07192715B2

公开(公告)日：2007-03-20

申请号：US10012756

申请日：2001-10-24

申请人： John B. Harley ,  Judith A. James

发明人： John B. Harley ,  Judith A. James

IPC分类号： G01N33/53 ,  A61K38/04 ,  A61K38/16 ,  A61K38/245

CPC分类号： C07K14/005 ,  A61K39/00 ,  C12N2710/16222 ,  C12N2710/16622 ,  G01N2800/24 ,  Y02A50/386 ,  Y02A50/414

摘要： Data consistent with autoimmune disease being caused by Epstein-Barr virus are shown. Based on this evidence, an effective vaccine would prevent the autoimmune disease in those vaccinated, modified or administered so that the vaccine is not itself capable of inducing autoimmune disease. In the case of anti-Sm, structures to be avoided in an Epstein-Barr virus-derived vaccine have been identified. Differences have been identified in the immune responses to Epstein-Barr infection between individuals who develop a specific autoimmune disease and those who do not. These differences are used to distinguish those who are at greater risk for developing specific autoimmune diseases from those who are a lesser risk. Assuming Epstein-Barr virus causes autoimmune disease and that Epstein-Barr virus remains latent in the patient for life, reactivation of the virus from the latent state is important in generating or maintaining the autoimmune response that culminates in autoimmune disease. Cells infected with latent virus may also encourage autoimmunity. Based on the understanding that reactivation or latency are important to produce or sustain autoimmunity, then therapies directed against Epstein-Barr virus will also be effective therapies for the autoimmune manifestations of disease for which Epstein-Barr virus is responsible.

摘要翻译： 显示与Epstein-Barr病毒引起的与自身免疫性疾病相一致的数据。 基于这一证据，有效的疫苗将防止那些接种，修饰或施用的自身免疫疾病，使得疫苗本身不能诱导自身免疫性疾病。 在抗Sm的情况下，已经鉴定了在爱泼斯坦 - 巴尔病毒来源的疫苗中避免的结构。 在发展特异性自身免疫性疾病的个体与不发生特异性自身免疫性疾病的个体之间的爱泼斯坦 - 巴尔病毒感染的免疫应答中已经鉴定出差异。 这些差异用于区分发展特定自身免疫性疾病风险较高的人群与风险较小者。 假设爱泼斯坦 - 巴尔病毒导致自身免疫性疾病，并且爱泼斯坦 - 巴尔病毒在患者身上保持潜伏，病毒从潜在状态的再激活对于产生或维持自身免疫应答至关重要，其最终导致自身免疫性疾病。 感染潜伏病毒的细胞也可能会鼓励自身免疫。 基于认识到再激活或延迟对于产生或维持自身免疫是重要的，那么针对爱泼斯坦 - 巴尔病毒的疗法也将成为爱泼斯坦 - 巴尔病毒负责的疾病的自身免疫表现的有效疗法。

公开(公告)号：US5719064A

公开(公告)日：1998-02-17

申请号：US944143

申请日：1992-08-31

申请人： R. Hal Scofield ,  John B. Harley

发明人： R. Hal Scofield ,  John B. Harley

IPC分类号： A61K38/00 ,  C07K14/195 ,  C07K14/74 ,  G01N33/543

CPC分类号： C07K14/195 ,  C07K14/70539 ,  A61K38/00

摘要： It has been determined that HLA B27 is related to proteins of the Gram negative enteric bacteria. The hypervariable regions of the HLA B alleles were compared to the known sequenced proteins for short consecutive amino acid identities. It was found that, unique to the HLA B alleles,, HLA B27 shares an unexpected number of hexapeptides and pentapeptides with Gram negative bacteria proteins. The proteins from enteric organisms that share sequence with B27 tend to have sequences that satisfy protein sequence motifs which are thought to predict binding to B27. In addition, there is a sequence in B27, LRRYLENGK, which is predicted to bind as a peptide to B27. Binding of this peptide to B27 has been demonstrated. The disclosed peptides are useful for diagnostic and therapeutic purposes and can be used to design additional peptides from Gram negative enteric organisms can be identified to be important in the spondyloarthropathies. These peptides and their analogs can be used to screen for antibodies, and more importantly, T cells reactive with the peptides, which are indicative of the spondyloarthropathies.

摘要翻译： 已经确定HLA B27与革兰氏阴性肠细菌的蛋白质相关。 将HLA B等位基因的高变区与已知测序的蛋白质进行比较以获得短的连续氨基酸同一性。 已经发现，HLA B等位基因特有的HLA B27与革兰氏阴性细菌蛋白质共享了意想不到的数量的六肽和五肽。 来自与B27共享序列的肠道生物体的蛋白质倾向于具有满足蛋白质序列基序的序列，这些序列被认为预测与B27的结合。 此外，B27中有一个序列，LRRYLENGK被预测作为肽结合到B27上。 已证明该肽与B27的结合。 所公开的肽可用于诊断和治疗目的，并且可用于设计来自革兰氏阴性肠道生物体的附加肽可以在脊椎关节病中被鉴定为重要的。 这些肽及其类似物可用于筛选抗体，更重要的是，与肽反应的T细胞，其指示脊柱关节病。