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METHOD FOR PREDICTING GRAFT-VERSUS-HOST DISEASE (GVHD) AND COMPUTER FOR PREDICTING GVHD

Foreign code F210010300
File No. (S2019-0423-N0)
Posted date 2021年1月29日
Country 世界知的所有権機関(WIPO)
International application number 2020JP018225
International publication number WO 2020250593
Date of international filing 令和2年4月30日(2020.4.30)
Date of international publication 令和2年12月17日(2020.12.17)
Priority data
  • 特願2019-108657 (2019.6.11) JP
Title METHOD FOR PREDICTING GRAFT-VERSUS-HOST DISEASE (GVHD) AND COMPUTER FOR PREDICTING GVHD
Abstract The present invention addresses the problem of providing a method for predicting a graft-versus-host disease (GVHD) and a computer for predicting a GVHD. This method for predicting a GVHD comprises: measuring the concentration of a soluble DNAM-1 in serum from a recipient; and performing an analysis by using a mathematical model, assuming that the concentration of the soluble DNAM-1 is the sum of the concentration x1 of a soluble DNAM-1 which is transiently released from a donor-derived lymphocyte, the concentration x2 of a soluble DNAM-1 which is constantly released from a donor-derived lymphocyte, and the concentration x3 of a soluble DNAM-1 which is released from a recipient-derived lymphocyte.
Outline of related art and contending technology BACKGROUND ART
Hematopoietic stem cell transplantation is directed to the eradication of tumor cells or normalization of myeloid function for hematopoietic tumors such as leukemia and malignant lymphoma. Hematopoietic stem cells are the mother cells of all hematopoietic cells that have the ability to produce mature blood cells such as red blood cells and white blood cells from a single cell, that is, multipotent, and have the ability to self-renewal. In order to eradicate tumor cells such as leukemia and lymphoma, it is possible to restore normal hematopoietic function by transplanting hematopoietic stem cells after a large amount of chemotherapy and radiotherapy.
Serious side effects following stem cell transplantation are graft versus host disease (graft-versus-host disease,) abbreviated as GVHD. Among hematopoietic stem cell transplantation, particularly) abbreviated as allogeneic hematopoietic stem cell transplantation (allogenic hematopoietic cell transplantation, allo-HSCT; Early complications may be acute graft-versus-host disease (acute graft-versus-host disease, acute GVHD, or) abbreviated as aGVHD. Acute GVHD represents a human leukocyte antigen (HLA: in which activated T cells from donor (transplant provider) present in transplant cells are expressed on the leukocyte surface of recipient (patient). (Non-Patent Document 1) produced by a donor activated T cell having a cytotoxic effect damaging a recipient cell by recognizing human leukocyte antigen) and considering the human leukocyte antigen) to be non-self. In patients considered to have developed acute GVHD, digestive symptoms such as fever, episodic rash (skin rash) of the limbs, face, and torso, liver damage associated with elevated bilirubin, abdominal pain, and diarrhea are observed. Diagnosis of GVHD is usually made by pathological searching of biopsies of skin, liver, and large intestine, although pathological findings are sometimes not typical. In addition, (Non-Patent Document 2), which often makes it difficult to acquire pathological materials and, in practice, experiences little to little diagnosis due to clinical symptoms.
Steroid administration is generally selected as an initial therapy for acute GVHD. Administration of steroids is an effective method of treatment for acute GVHD, but administration of steroids may also combine serious side effects such as bacterial and viral infections, and the timing of the start of treatment and the dosage thereof must be carefully determined. On the other hand, there is a dilemma that is lethal when the start of treatment of acute GVHD is delayed, and in the clinical setting, how to diagnose and intervene acute GVHD at an early stage is an important problem relating to the success or failure of transplantation.
As a method of predicting the likelihood of developing acute GVHD, (Patent Document 1) has been developed to examine soluble DNAM-1 levels and examine changes in soluble DNAM-1 levels over time. DNAM-1 is a membrane protein found by Astringency, one of the present inventors, and DNAM-1 (CD226) is strongly expressed in activated T cells, NK cells, and the like having cytotoxic activity; (NpL 2), which has been suggested to recognize and adhere ligands expressed on human tumor cells and the like, and play an important role in inducing cytotoxicity of target tumor cells. Some of the DNAM-1 molecules whose expression in activated T cells is enhanced are cleaved from the cell membrane and released as soluble DNAM-1 in the bloodstream. Thus, soluble DNAM-1 molecules that are enriched in recipient blood have been considered to be derived from donor leukocyte cells.
According to the method of Patent Document 1, when the soluble DNAM-1 concentration in the blood is a value higher than the normal range, acute GVHD can be developed, close to, or possibly leading to the development of acute GVHD, but the accuracy of the prediction is not satisfactory. (Non-Patent Document 3), which has been said that the serum soluble DNAM-1 concentration in patients who developed acute GVHD was already higher than that in patients who did not develop acute GVHD from seven days prior to allogeneic hematopoietic stem cell transplantation, has been reported, and that the serum soluble DNAM-1 concentration may be an indicator of the development of acute GVHD. However, the kinetics of blood soluble DNAM-1 were unknown, and acute GVHD developed or could not predict its severity. That is, to date, there is no way to predict the likelihood or severity of developing graft-versus-host disease following bone marrow transplantation in advance.
  • Applicant
  • ※All designated countries except for US in the data before July 2012
  • UNIVERSITY OF TSUKUBA
  • Inventor
  • SHIBUYA Akira
  • SHIBUYA Kazuko
  • GOSHIMA Yuki
IPC(International Patent Classification)
Specified countries National States: AE AG AL AM AO AT AU AZ BA BB BG BH BN BR BW BY BZ CA CH CL CN CO CR CU CZ DE DJ DK DM DO DZ EC EE EG ES FI GB GD GE GH GM GT HN HR HU ID IL IN IR IS JO JP KE KG KH KN KP KR KW KZ LA LC LK LR LS LU LY MA MD ME MG MK MN MW MX MY MZ NA NG NI NO NZ OM PA PE PG PH PL PT QA RO RS RU RW SA SC SD SE SG SK SL ST SV SY TH TJ TM TN TR TT TZ UA UG US UZ VC VN WS ZA ZM ZW
ARIPO: BW GH GM KE LR LS MW MZ NA RW SD SL SZ TZ UG ZM ZW
EAPO: AM AZ BY KG KZ RU TJ TM
EPO: AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR
OAPI: BF BJ CF CG CI CM GA GN GQ GW KM ML MR NE SN ST TD TG
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