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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 Jan 29, 2021
Country WIPO
International application number 2020JP018225
International publication number WO 2020250593
Date of international filing Apr 30, 2020
Date of international publication Dec 17, 2020
Priority data
  • P2019-108657 (Jun 11, 2019) 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.
Scope of claims (In Japanese)[請求項1]
 レシピエントの血清中の可溶性DNAM-1濃度を測定し、
 前記可溶性DNAM-1濃度は、ドナー由来リンパ球から一過性に放出される可溶性DNAM-1濃度x 1、ドナー由来リンパ球から恒常的に放出される可溶性DNAM-1濃度x 2、およびレシピエント由来リンパ球から放出された可溶性DNAM-1濃度x 3の総和であると仮定し、数理モデルを用いて解析することを含む、移植片対宿主病(GVHD)の予測方法。

[請求項2]
 レシピエントの血清中の可溶性DNAM-1濃度を測定し、
 ある時点(t)における前記可溶性DNAM-1濃度は、ドナー由来リンパ球から一過性に放出される可溶性DNAM-1濃度x 1(t)、ドナー由来リンパ球から恒常的に放出される可溶性DNAM-1濃度x 2(t)、およびレシピエント由来リンパ球から放出された可溶性DNAM-1濃度x 3(t)の総和であると仮定して、x 1(t)、x 2(t)、およびx 3(t)を算出し、式(1)によりR day_nを算出することを含む、移植片対宿主病(GVHD)の予測方法。
[数1]
(省略)
〔式(1)中、day_nは、移植後の日数である。〕

[請求項3]
 前記予測方法は、GVHD発症および重症度の少なくとも一方の予測方法である請求項2に記載の予測方法。

[請求項4]
 前記GVHDは、同種造血幹細胞移植の合併症である、請求項2または3のいずれか1項に記載の予測方法。

[請求項5]
 前記x 1(t)は、式(2)により算出されるものである、請求項2~4のいずれか1項に記載の予測方法。
[数2]
(省略)
〔式(2)中、f(t)は単峰性の関数、かつf(∞)=0であり、μは可溶性DNAM-1の消失速度である。〕

[請求項6]
 前記x 2(t)は、式(3)により算出されるものである、請求項2~5のいずれか1項に記載の予測方法。
[数3]
(省略)
〔式(3)中、g(t,μ)は式(4)を満たし、μは可溶性DNAM-1の消失速度である。〕
[数4](省略)

[請求項7]
 前記x 3(t)は、式(5)により算出されるものである、請求項2~6のいずれか1項に記載の予測方法。
[数5]
(省略)
〔式(5)中、μは可溶性DNAM-1の消失速度である。〕

[請求項8]
 前記x 1(t)は式(6)により、かつ、前記x 2(t)は式(7)により、算出されるものである、請求項2~7のいずれか1項に記載の予測方法。
[数6]
(省略)
〔式(6)中、λは、ガンマ分布の調整パラメータ、kはガンマ分布の形状母数、θはガンマ分布の尺度母数、μは可溶性DNAM-1の消失速度である。〕
[数7]
(省略)
〔式(7)中、rは可溶性DNAM-1の産生速度、μは可溶性DNAM-1の消失速度、Nはx 2の推定最大濃度である。〕

[請求項9]
 レシピエントの血清中の可溶性DNAM-1濃度を測定し、
 ある時点(t)における前記可溶性DNAM-1濃度は、ドナー由来リンパ球から一過性に放出される可溶性DNAM-1濃度x 1(t)、ドナー由来リンパ球から恒常的に放出される可溶性DNAM-1濃度x 2(t)、およびレシピエント由来リンパ球から放出された可溶性DNAM-1濃度x 3(t)の総和であると仮定して、x 1(t)、x 2(t)、およびx 3(t)を算出し、式(1)によりR day_nを算出することを含む、移植片対宿主病(GVHD)を予測するコンピュータープログラム。
[数8]
(省略)
〔式(1)中、day_nは、移植後の日数である。〕
  • 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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