Method for matching donor bone marrow transplant to recipient

Abstract

The invention relates to medicine, and more particularly to methods for matching a donor bone marrow transplant to a recipient, and can be used for determining the compatibility of genetic substances of transplants. The problem addressed is that of identifying a suitable donor. According to the invention, values of ten gene loci А, В, С, DRB1, DQB1 on recipient and donor chromosomes are obtained using HLA typing technology and said values are statistically processed to find the best compatibility between donor and recipient bone marrow. The technical result is that of achieving the intended purpose by means of the invention.

Description

[0001] METHOD OF SELECTION OF BONE MARROW TRANSPLANT FROM DONORS TO RECIPIENTS

[0002] The field of technology to which the invention relates.

[0003] The invention relates to medicine, specifically to methods for matching bone marrow transplants from donors to recipients, and can be used to establish compatibility of the transplants' gene substances. The main challenge is finding a suitable donor.

[0004] The following terms are used in this description:

[0005] HLA typing (tissue typing) is the determination of genes or antigens of the inherited genetic system located on chromosome 6, one of the functions of which is the recognition and rejection of foreign tissues and organs.

[0006] BMT - bone marrow transplantation.

[0007] HSCT – homopoietic stem cell transplantation.

[0008] State of the art

[0009] Bone marrow transplantation and homopoietic stem cell transplantation are used to treat severe forms of leukemia and other malignant, oncological blood diseases. Approximately 20,000 patients in Russia require transplantation annually.

[0010] The central task in transplantation (BMT and HSCT) is to establish compatibility between the gene substances of the transplant recipients. The main challenge is finding a suitable donor.

[0011] Compatibility of donor and recipient transplants is determined using HLA typing technology, which involves identifying genes or antigens of the inherited genetic system located on the sixth chromosome, one of whose functions is the recognition and rejection of foreign tissues and organs.

[0012] HLA typing technology identifies loci—locations (in a sense, coordinates)—of a specific gene on a chromosome. Compatibility is determined from at least five genes identified by HLA technology (HLA-A*, HLA-B*, HLA-C*, HLA-DRB1*, and H-DQB1*). Letters and letter combinations with asterisks denote the following numerical combinations, as in Table 1 below, for a recipient requiring a BMT transplant.

[0013] Table 1. High-resolution HLA typing of 1 SBT sample urgently (loci A, B, C, DRB1, DQB1)

[0014] As we can see, each locus represents the location of two genes on the chromosome, for example, locus A is 02:01:01 32:01:01 .

[0015] The results of a specific recipient's HLA typing are included in a common international donor database for manual matching of loci between specific recipients and donor populations. Currently, there are guidelines regulating the use of HLA typing of bone marrow donors for working with data on loci of a given recipient.

[0016] In total, five basic principles of HLA typing of bone marrow donors in medical interactions with patients have been formulated.

[0017] 1. HLA-identical related donor - a donor who inherits common HLA haplotypes with the patient from the same parents (HLA haplotype is a set of HLA genes located on the same chromosome.)

[0018] 2. Partially compatible related donor - a donor who differs from the patient in one HLA gene, provided that the donor and recipient are siblings (Sibling - a full brother or sister - children of the same parents).

[0019] 3. Haploidentical related donor - a donor who inherits one HLA haplotype in common with the patient, subject to compatibility of at least 50.0% for 10 or more HLA genes. 4. Fully compatible unrelated donor - a donor who completely matches the patient in at least 10 out of 10 HLA genes (HLA-A* HLA-B*, HLA-C*, HLA-DRB1* HLA-DQB1* - where the asterisk denotes numerical values, for example: 02:01:01).

[0020] 5. Partially compatible unrelated donor - a donor compatible with the patient by 70.0 - 90.0% for 10 or more HLA genes (HLA-A* HLA-B* HLA-C*, HLA-DRB1* HLA-DQB1* - where the asterisk denotes digital values, for example: 02:01:01).

[0021] This knowledge is fundamentally important for finding compatible bone marrow from donor to recipient to avoid unexpected immune system rejection reactions. It is especially important for software development for the application of digital technologies in medicine.

[0022] Disclosure of invention.

[0023] Based on this original observation, the present invention primarily aims to propose a method for matching bone marrow transplants from donors to recipients, aimed at establishing the best compatibility of the gene substances of the donor and recipient transplants, which is precisely the technical problem being solved. The achievable technical result is the invention's realization of the stated purpose.

[0024] To achieve this goal: a. the values ​​of five gene loci A, B, C, DRB1, DQB1 are obtained using HLA typing technology on the recipient's chromosome, two measurements each, for a total of 10 measurements; b. the values ​​of five gene loci A, B, C, DRB1, DQB1 are obtained using HLA typing technology on the chromosome of each of the donors, two measurements each, for a total of 10 measurements;; c. a matrix of gene loci values ​​A, B, C, DRB1, DQB1 of the recipient and donors is formed, consisting of rows with the values ​​of the loci of the recipient and all donors, and columns, the first of which corresponds to the recipient, and each of the following corresponds to its own donor, if the loci of the recipient and donors match in the matrix, "1" is put, and if not, then "0"; d. the data of the specified matrix are processed using a multiple linear regression system, considering the dependent variable Y to be the values ​​for the recipient, and the independent variables Xi, X2, X3, ... to be the values ​​for the donors, i.e. for each pair Y and X п obtain the coefficient of determination Rn 2 , f. choose the donor whose R value n 2 will be maximum and at the same time exceed 75.0% if all R n 2 does not exceed 75.0%, a decision is made on the incompatibility of the bone marrow of the donor and recipient.

[0025] These advantageous characteristics make it possible to decide on the best compatibility of donor and recipient bone marrow.

[0026] Implementation of the invention.

[0027] The method for selecting a bone marrow transplant from a donor to a recipient is carried out as follows. (An example is given that does not limit the application of the invention.)

[0028] Example 1.

[0029] Let's continue the example according to the data in Table 1.

[0030] Table 1. High-resolution HLA typing for the recipient of the urgent SBT sample (loci A, B, C, DRB1, DQB1)

[0031] We will also make the same table for donors.

[0032] Table 2. High-resolution HLA typing for donors, urgent SBT sample (loci A, B, C, DRB1, DQB1)

[0033] Note: The columns indicate genes: A, B, C, DRB1, DQB1. The rows indicate recipient numbers. The number of donors with these loci in the databases exceeds 200,000.

[0034] According to the invention, we present the same data on loci in a form in which the digital combinatorial transformation does not change the essence of HLA typing, but creates opportunities for accurate, efficient and rapid selection of a donor for a recipient.

[0035] The digital description of the frequency of loci in the recipient and donors is implemented using binary codes "0" or "1." If the gene location of the donor and patient matches, the number "1" is entered in the matrix table; otherwise, "0" is entered. This process continues throughout the entire data set. Let's represent this combinatorial solution as matrix table 3.

[0036] Table 3. Matrix table of data on genes and locations of donors and recipients.

[0037] Note: In columns 1 through p, the first digit denotes the recipient number, while the remaining column numbers indicate the numbers of donors among whom there is a chance that a suitable bone marrow donor will be found. In the "locus" column, the letter designations "pp:pp:pp" represent the numeric designations of gene positions on the chromosome, for example, 03:02:01. There may be more than two such designations, since there may be a whole population of donors. The number of loci is determined specifically, depending on the number of donors and non-matching loci. Accordingly, "0" denotes the absence of identical loci, and "1" denotes that the loci, for example, match those of a given donor and recipient.

[0038] According to the above matrix model, specific matrices are created with data on the recipient and donor loci.

[0039] The matrix below (Table 4) represents a collection of specific clinical data for the loci of one recipient and nine donors. The number of loci for specific genes is determined by the diversity of loci in specific donors. Table 4. Clinical loci matrix 10 / 24

[0040] Note: The column with the bold number 1 indicates a recipient requiring a bone marrow transplant. Columns 2 through 10 represent bone marrow donor data. The clinical locus matrix data were processed using a multiple linear regression system (Y = b0 + b-|Xi + b2X2... b n X n ), where the dependent variable “1” is accepted under the sign Y - the recipient, and under the sign Xi, X2...X П dependent variables are designated - bone marrow donors.

[0041] The following calculation results are obtained. The dependent variable (V), which denotes the recipient in need of a bone marrow transplant, is 100.0% determined by the value of the independent variable—the donor—patient No. 9. The values ​​of the measurements of the independent variables—the remaining donors (X1, X3, X4, X5, X6, X7, Xe, X9)—are equal to zero.

[0042] In the case where, on the contrary, the dependent variable (Y) becomes the independent variable - donor - patient No. 9, and the independent variables are 1, 2, 3, 4, 5, 6, 7, 8, 100, then donor-patient No. 9 also depends 100.0% on the value of the already independent variable - donor-patient No. 1, and the values ​​of the remaining independent variables (Xi, Xz, X4, X5, X6, X7, Xe, Xg) are equal to zero.

[0043] Thus, using statistical methods, a donor for a compatible bone marrow transplant can be found quite quickly and efficiently.

[0044] Industrial applicability.

[0045] The proposed method for selecting a bone marrow transplant from donors to a recipient can be implemented by a specialist in practice and, when implemented, ensures the implementation of the stated purpose, which allows us to conclude that the invention meets the “industrial applicability” criterion.

[0046] This invention can be used in the selection of bone marrow transplants from donors to recipients.

Claims

CLAUSES OF THE INVENTION A method for selecting a bone marrow transplant from donors to a recipient, which comprises a. HLA typing of five gene loci A, B, C, DRB1, DQB1, including at least two measurements for each locus on the recipient chromosome and at least two measurements for each locus on the chromosome of each of the donors; b. forming a matrix of values ​​of the gene loci A, B, C, DRB1, DQB1 of the recipient and donors, consisting of rows with the values ​​of the loci of the recipient and all donors, and columns, the first of which corresponds to the recipient, and each of the following corresponds to the donor, if the loci of the recipient and donors match in the matrix, "1" is put, and if not, then "0"; c. The data of the specified matrix are processed using a multiple linear regression system, considering the dependent variable Y to be the values ​​for the recipient, and the independent variables X1, X2...Xп to be the values ​​for the donors, d. For each pair of Y and Xп, the determination coefficient Rn2, e, is obtained.They select the donor whose Rn2 value is the highest and at the same time exceeds 75.0%; if the total Rn2 does not exceed 75.0%, they decide on the incompatibility of the bone marrow of the donors and the recipient.

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