KR20170089309A - Method for diagnosing kidney allograft rejection using the frequency of CD4+CD25+ T cells in peripheral blood - Google Patents
Method for diagnosing kidney allograft rejection using the frequency of CD4+CD25+ T cells in peripheral blood Download PDFInfo
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Abstract
Description
The present invention relates to a method for diagnosing renal transplant rejection using the ratio of CD4 + CD25 + T cells in peripheral blood, and more particularly, Collecting a blood sample from a kidney transplant patient; (b) determining the ratio of CD4 + CD25 + T cells among CD4 + T cells present in the blood (CD4 + CD25 + T / CD4 + T cell); And (c) determining that a rejection reaction is present when the ratio of T cells in the identified kidney transplant patient is increased as compared with the control, and a method for detecting a marker of renal transplant rejection, And a composition for diagnosing rejection of kidney transplantation comprising an anti-CD25 antibody.
Renal transplantation is almost the only treatment for patients with end-stage renal disease (ESRD). The success rate of kidney transplantation is improved by the development of more potent immunosuppressive agents, but is still significantly affected by acute rejection and secondary infection (USRDS Annual Data Report 2012). Immunosuppressants should be used at optimal doses to reduce adverse reactions while suppressing rejection, and at the same time be accompanied by monitoring of appropriate immune responses to early detection of rejection at the initial stage after transplantation.
T-lymphocytes act as immunomodulators in kidney transplants. T-lymphocytes interact with antigen presenting cells and regulate T cell activity through a variety of signal transduction. The most important signal originates from a complex of TCR-CD3, MHC and peptide antigens. In addition, T cells are activated through a variety of other signal transductions that affect T cell activation and differentiation, and activated T cells are involved in inducing and maintaining renal transplant rejection (Sharpe AH., Immunol Rev. 229 (1): 5-11, 2009; Hall BM. Transplantation 51 (6): 1141-51, 1991). Immunohistochemical analysis revealed that monocyte-derived chemokines such as TNF-α and macrophage inflammatory protein-1a increased expression levels by T-cell activation, and that HLA-DR was detected in transplantation biopsy of transplant recipients with acute rejection (3): 708-17, 1986; Waltzer et al., Am J Transplant . 5 (3): 573-81, 2005. Bishop G et al., Kidney Int . .. W et al, Transplantation 43 (1): 100-5, 1987; Hall BM et al, Lancet 2 (8397):.. 247-51, 1984). It has been reported that the degree of allograft infiltration of monocytes and the level of expression of HLA-DR are associated with the degree of graft function abnormalities that occur during rejection in kidney transplant patients (Girlanda R et al. . Am J Transplant 8 (3) : 600-7, 2008). In addition, transplant patients with reduced HLA-DR expression in monocytes have been reported to be at increased risk for a variety of infections such as cytomegalovirus (CMV) infection (Reinke P et al., Transpl Infect Dis . 1 (3): 157-64, 1999).
Several studies using transplant models have shown that activated T cells in the alloimmune state (Waldmann H et al., Immunol Rev. 212: 301-13, 2006; Taylor PA et al., J Exp Med . 193 (11): 1311-8, 2001; Hara M et al., J Immunol . 166 (6): 3789-96, 2001) and monocytes (Le Meur Y et al, Transplantation 73 (8..):.. 1318-24, 2002; Jose MD et al, Transplantation 76 (7): 1015-2 , 2003), but the clinical significance of these cells in peripheral blood is unknown.
Therefore, it is necessary to develop diagnostic markers for immunological monitoring to evaluate the changes of T cell and mononuclear aggregation in various post-transplant conditions such as acute rejection and CMV infection and to diagnose transplant rejection in kidney transplant patients.
Therefore, the inventors of the present invention found that the ratio of CD4 + CD25 + / CD4 + T cells was closely related to the graft rejection response while studying the correlation between the graft rejection reaction and the circulating immune cells in the peripheral blood of kidney transplant patients Thus completing the present invention.
It is therefore an object of the present invention
In order to provide information necessary for diagnosis of rejection of renal transplantation,
(a) collecting a blood sample from a kidney transplant patient;
(b) determining the ratio of CD4 + CD25 + T cells among CD4 + T cells present in the blood (CD4 + CD25 + T / CD4 + T cell); And
(c) determining that a rejection reaction is present when the ratio of T cells in the identified kidney transplant patient is increased as compared with the control, and detecting the marker of rejection of kidney transplantation.
Another object of the present invention is
CD4 antibody and an anti-CD25 antibody to a subject in need thereof.
To achieve these and other advantages and in accordance with the purpose of the present invention,
In order to provide information necessary for diagnosis of rejection of renal transplantation,
(a) collecting a blood sample from a kidney transplant patient;
(b) determining the ratio of CD4 + CD25 + T cells among CD4 + T cells present in the blood (CD4 + CD25 + T / CD4 + T cell); And
(c) determining that a rejection reaction is present when the ratio of T cells in the identified kidney transplant patient is increased as compared with the control, and detecting the marker of rejection of kidney transplantation.
In order to achieve another object of the present invention,
There is provided a composition for diagnosing rejection of kidney transplantation comprising an anti-CD4 antibody and an anti-CD25 antibody.
Hereinafter, the present invention will be described in detail.
In order to provide information necessary for diagnosing rejection of renal transplantation,
(a) collecting a blood sample from a kidney transplant patient;
(b) determining the presence CD4 + T cells CD4 + CD25 + T cell ratio ( CD4 + CD25 + T / CD4 + T cell ); And
(c) determining that a rejection reaction is present when the ratio of T cells in the identified kidney transplant patient is increased compared to the control, and Ker The method comprising:
The step (a) is a step of collecting a blood sample from a kidney transplant patient.
The step (a) is a step of collecting a blood sample of a kidney transplant patient to provide information necessary for diagnosing whether a rejection has occurred in a kidney transplant patient. In order to more accurately diagnose the rejection reaction according to the method according to the present invention, the blood sample is preferably peripheral blood and is collected from the patient according to a known method for measuring the ratio or frequency of cells present in the blood, can do.
Blood samples from kidney transplant patients can be collected when there is a need to confirm rejection after renal transplantation, for example, clinical signs such as renal function deterioration after renal transplantation, and when rejection is suspected, It may also be taken at the time of indication biopsy to determine the severity of tissue damage in the kidney.
In step (b), CD4 + CD25 + T cells in CD4 + T cells present in blood collected from kidney transplant patients (CD4 + CD25 + T / CD4 + T cell) are identified.
T cells are also referred to as T-cells, T-cells, T lymphocytes, T-lymphocytes, and T lymphocytes. T cell receptors (TCRs) play an important role in cell-mediated immunity Means a white blood cell that expresses. (T cell), T cell (suppressor T cell), natural killer T cell, memory T cell, mucosal associated invariant T cell, and gamma delta T cell (γδ T cell).
'CD4' is an abbreviation for 'cluster of differentiation 4' and is a transmembrane glycoprotein expressed on the surface of various immune cells such as helper T cells, monocytes, macrophages and dendritic cells. CD4 specifically binds to class II MHC proteins and acts as a co-receptor for TCR in helper T-cells signaling to antigen-presenting cells. In the present invention, 'CD4 +' means that CD4 protein is expressed.
CD25 is an abbreviation for cluster of
In step (b), the ratio of CD4 + CD25 + T cells among the CD4 + T cells present in the blood collected from kidney transplant patients (CD4 + CD25 + T / CD4 + T cell) is determined. In the present invention, the 'ratio' of the specific T cell, that is, the CD4 + CD25 + cell is used in the same meaning as the 'frequency', and is expressed as a percentage (%) with respect to CD4 + T cells.
The method of confirming the ratio of the T cells present in the blood sample can be selected without limitation as long as it is commonly used in the art. Most commonly, the ratio (or frequency) of the T cells in the blood can be measured using flow cytometry. A marker (preferably a protein expressed on the cell surface) that is expressed at a specific or high level in a desired cell population is selected, and specifically bound to the marker, and a fluorescently labeled antibody is reacted with blood cells . Blood cells to which the fluorescence-labeled antibody is bound are classified according to the labeled fluorescence by using a fluorescence activated cell sorter (FACS), and the number of cells labeled with a specific fluorescence is measured, .
Therefore, in order to confirm the ratio of CD4 + CD25 + / CD4 + T cells by flow cytometry, blood cells were reacted with anti-CD4 antibody and anti-CD25 antibody labeled with different fluorescence, and the cells were classified into FACS according to labeled fluorescence (CD4 + T cell) expressing CD4, and the ratio of T cell (CD4 + CD25 + T cell) expressing CD25 and CD4.
The step (b) further comprises the step of analyzing a protein or a cell surface marker to differentiate T cells from other types of immune cells to further confirm that the cells expressing CD4 are T cells . This process is involved in calculating the ratio of CD4 + CD25 + / CD4 + T cells according to the present invention, considering that the CD4 protein is expressed in other types of cells besides T cells, To prevent it. For example, TCR is T cell specific and CD14 is expressed in macrophages, neutrophils and some dendritic cells. It is possible to distinguish T cells from other immune cells by examining the expression of these cell-specific proteins in the T cells of renal transplant recipients.
In the step (c), the ratio of CD4 + CD25 + / CD4 + T cells in the kidney transplant patient confirmed in step (b) is compared with the control group. If the ratio is increased, it is determined that rejection is present in the kidney transplant patient. The control group may be a patient group that has not been found to have rejection after kidney transplantation.
'Renal allograft rejection' refers to a series of immune responses that occur when a donor's kidney transplant recipient's immune system recognizes the transplantation kidney as an external antigen. Acute rejection (acute rejection) and chronic rejection (chronic rejection) can be classified as. Acute rejection usually occurs within a few days to six months after renal transplantation, with fever, tenderness at the transplantation site, decreased urine, and decreased renal function. Cellular immunity and humoral immunity are involved and cause tissue damage of the transplant kidney. Histologically, renal tubular inflammation and endothelial cell inflammation are seen, and mononuclear cell carcinoma of the kidney and tubular necrosis are observed. Chronic rejection occurs after 6 months after transplantation and is characterized by gradual renal dysfunction accompanied by proteinuria and hypertension. If vascular inflammation and fibrosis occur in the grafted kidney due to the immune rejection of the recipient, the renal function is worsened and the kidney function is progressed as a whole due to overload of the healthy glomeruli.
The method according to the present invention can be more usefully used for diagnosing acute rejection even in rejection of renal transplantation.
In the examples of the present invention, it was confirmed that the ratio of CD4 + CD25 + / CD4 + T cells found in the peripheral blood of the patient group showing acute rejection was significantly increased as compared with the kidney transplantation group not showing the transplantation rejection (Table 5 Reference). The kidney transplantation patients who were diagnosed to have acute cellular rejection by tissue biopsy showed renal transplantation with creatinine level of 3.06mg / dL after renal transplantation. There was a statistically significant difference in the proportion of CD4 + CD25 + / CD4 + T cells compared to the toxic or non-specific pathology group. These results suggest that the ratio of CD4 + T cell subgroups expressing CD25, that is, the ratio of CD4 + CD25 + / CD4 + T cells, can be used as a marker for diagnosing rejection, especially acute rejection, in renal transplant patients.
In another embodiment of the present invention, the ROC curve of CD4 + CD25 + / CD4 + T cell ratio as a marker for diagnosing rejection in kidney transplant patients was analyzed. As a result, the ratio of CD4 + CD25 + / CD4 + T cell was 4.8% cutoff), the acute rejection can be predicted with a sensitivity of 75% and a specificity of 43.0% (see FIG. 2A). In addition, in the ROC analysis with additional confounding variables, acute rejection was predicted with a sensitivity of 75% and an accuracy of 68.4% when the cutoff of CD4 + CD25 + / CD4 + T cell ratio was 5.8% ). The area under the curve before and after adjusting the confounding variables were calculated to be 0.704 and 0.764, respectively, indicating that the ratio of CD4 + CD25 + / CD4 + T cells is a predictor of acute rejection.
Therefore, when the method of the present invention is carried out to diagnose a rejection reaction in a kidney transplant patient, the ratio of CD4 + CD25 + / CD4 + T cells in a kidney transplant patient in the step (c) And the number of patients with renal transplantation was higher than 4.8% and less than 100%.
The present invention also relates to an anti- CD4 Antibodies and anti- CD25 There is provided a composition for diagnosing a rejection reaction of a kidney transplant containing an antibody.
The composition of the present invention comprising a combination of the above antibodies may be used to identify the percentage of cells expressing CD25 in T cells expressing CD4 in blood, preferably peripheral blood, of a patient to diagnose a rejection reaction in a kidney transplant patient will be. As described above, the ratio of CD4 + CD25 + / CD4 + T cells can be used as a marker for diagnosing rejection after kidney transplantation. The antibody is not particularly limited as long as it is capable of specifically binding to CD4 and CD25 proteins, respectively.
Furthermore, the composition according to the present invention is a substance that binds to a cell surface marker capable of distinguishing T cells from other types of immune cells to further confirm that the cells detected as antibodies to CD4 or CD25 are T cells or Antibodies may be additionally included. Since CD4 proteins are known to be expressed in other types of immune cells besides T cells, it may be necessary to distinguish these different types of cells from T cells so that they are not included in the assay according to the present invention. For example, TCR is T cell specific. CD14 is also expressed mainly in macrophages, neutrophils and some dendritic cells. By confirming the expression of these cell-specific proteins, it is possible to distinguish T cells from other immune cells.
The antibody may also be labeled with a marker for detection. When flow cytometry analysis using FACS is performed to confirm the ratio of CD4 + CD25 + / CD4 + T cells, the antibody contained in the composition according to the present invention is preferably labeled with appropriate fluorescence. In addition, antibodies to CD4 and CD25 (and marker proteins, if they additionally contain antibodies to other marker proteins) can be detected with different wavelengths of fluorescence or multiple fluorescent substances that can be distinguished by FACS Should be labeled. Fluorescence (cy2, cy3, cy5, cy7 etc.), fluorescein such as FITC, phycoerythrin (PE) and fluorescence of alexa fluor series (Alexa fluor 405, 488, 647, 700 Etc.), and two of these fluorescers, for example, PE and cy5, may be labeled as an antibody.
Accordingly, the present invention provides a method and a composition for diagnosing transplantation rejection by measuring the ratio of CD4 + CD25 + T cells in total CD4 + T cells present in the blood of a kidney transplant patient. Increases in the proportion of CD4 + CD25 + / CD4 + T cells in the blood of kidney transplant patients can diagnose kidney transplant rejection with up to 75% sensitivity and 68.4% accuracy.
Figure 1 shows changes in T-lymphocyte subpopulations and HLA-DR + mononuclear cells before and after kidney transplantation (KT) (before KT). The median, interquartile range, and range were expressed as box and whisker plots. MFI represents the mean fluorescence intensity, and * represents p < 0.001.
Figure 2 shows the receiver-operating characteristic curve (ROC) analysis of CD4 + CD25 + / CD4 + T cells as a marker of acute rejection. Figure 2A shows the ROC after adjusting the confounding variables, Figure 2B shows the ROC after adjusting.
Hereinafter, the present invention will be described in detail.
However, the following examples are illustrative of the present invention, and the present invention is not limited to the following examples.
<Experimental Method>
Clinical trial patient
This study was conducted on adult patients over 20 years of age who underwent ABO-compatible single-organ kidney transplantation from surviving or deceased donors. Patients who received immunosuppressive therapy in the previous month, patients with a history of malignancy other than melanoma skin cancer for 5 years before transplantation, patients who had severe injury or major surgery last month, patients with infection such as HIV or viral infection, Patients with immune or blood disease were excluded from the study. Prior to clinical study participation, all patients submitted informed consent. The protocols of clinical trials were reviewed and approved by the Institutional Review Board of Kyungpook National University Hospital.
Immunosuppressive therapy
All patients underwent induction treatment with the IL-2 receptor (IL-2R) antibody. Immunosuppression therapy following renal transplantation was based on standard triple therapy including corticosteroids, calcineurin inhibitor (CNI) and mycophenolate mofetil. Corticosteroid therapy was intravenously injected with 500 mg methylprednisolone at the time of surgery and then decreased by oral administration of 5 mg / day prednisolone until 6 months later. The lowest level of Tacrolimus was adjusted to 8 to 12 ng / mL for the first 3 months and to 5 to 8 ng / ml thereafter. Cyclosporine levels were adjusted to 250 to 300 ng / ml for the first 3 months and then to 100 to 150 ng / ml. Mycophenolate mofetil was administered at 1.0 to 2.0 g daily fixed dose.
Experimental Design
A single-center study for prediction and observation assessed the efficacy of monitoring immune responses in diagnosing acute cellular rejection and CMV infection. For renal transplantation of surviving donors, peripheral blood of the patient was collected 1 week before and 2 weeks after transplantation. In the case of a donor kidney transplantation, the peripheral blood of the patient was collected before administration of the immunosuppressant on the transplantation day and 2 weeks after the transplantation. In addition, peripheral blood was collected 2 weeks after the transplantation follow-up, at the time of diagnosis, and biopsy confirmed the acute cellular rejection and CMV infection. The diagnosis of acute cellular rejection was confirmed by a graft kidney
T cell And monocytes Subgroup Flow cytometry
CD3 +, CD4 +, CD8 +, CD25 + and HLA-DR + T cells and HLA-DR + monocytes in peripheral blood were analyzed by flow cytometry. Whole blood samples were stained with fluorochrome conjugated monoclonal antibody in a dark room at room temperature for 20 minutes. Anti-CD4-PE (clone HW8a), anti-CD3-PE (clone UCHT1), anti-CD4-PE-Cy5 (clone RPA-T4) -HLA-DR-FITC (clone TU36) (BD Biosciences, San Jose, Calif.). Data are expressed as percentage and mean fluorescence intensity (MFI). After the reaction, red blood cells were dissolved in a dissolution solution (DN RBC Lysis Buffer, DiNona Inc., Seoul, Korea). Cells were washed once with PBS and redispersed and analyzed with a FACSCalibur flow cytometer and CellQuest software (BD Biosciences).
Statistical analysis
Using the Mann-Whitney U test (G * Power program version 3.1.9.2, Franz Paul, Kiel, Germany), the difference in CD4 + CD25 + T cell ratios between 0.8 power and 0.05 type I error was measured. Patients were needed. Data are presented in median or percentage. Because the variables to be analyzed do not follow the normal distribution, the difference between the T-lymphocyte subpopulation group and the mononuclear cell percentage was judged using the Mann-Whitney U test between the two groups and the Kruskal-Wallis test between the three or more groups. The Wilcoxon signed rank test was used to compare mononuclear cell percentage with T-lymphocyte subpopulations before and after kidney transplantation. The percentage of optimal T cell subpopulations to determine the cutoffs for the highest sensitivity and accuracy in discriminating acute cellular rejection was analyzed using receiver operating characteristic (ROC) curves. Thereafter, ROC was adjusted according to patient's sex, age, donor type, basal kidney disease, calcineurin inhibitor type and mismatch. Statistical analysis was performed using SPSS version 19.0 (SPSS, Chicago, IL) and SAS system version 9.2 for Windows (SAS Institute Inc., Cary, NC). p <0.05 was considered statistically significant.
< Example 1> Kidney transplant patients involved in clinical trials
This study was conducted on 123 renal transplant recipients (76 males, 47 females, median age of 46 years [range 24 to 67]).
The basic information of the patients participating in this study is summarized in Table 1 . The most common cause of end stage renal disease (ESRD) was chronic glomerulonephritis (61.8%). All patients were the first transplant except for one patient who received the second transplant. The median follow-up period after transplantation was 55.0 months [range 3.4 to 93.8]. 115 patients (93.5%) received triple therapy including tacrolimus, and 8 patients (6.5%) received cyclosporine-containing triple therapy.
< Example 2> Changes in immune cell ratio before and after kidney transplantation
We examined the changes in the percentage of immune cells present in the peripheral blood of renal transplant recipients before and after kidney transplantation.
The baseline frequencies of the T-lymphocyte subgroup and HLA-DR + monocyte are summarized in Table 2 . There was no significant difference in the proportion of these cells among the groups classified according to sex, age, donor type and ESRD in kidney transplant patients. The ratio of CD4 + CD25 + / CD4 + T cells, CD8 + CD25 + / CD8 + T cells and HLA-DR + monocytes was significantly lowered after 2 weeks of transplantation compared with before transplantation ( FIG. 1 , 11.95% [range 0.50-29.40% ] vs. 5.10% [range 0.1033.3%]; 0.90% [range 0.00-5.80%] vs. 0.60% [range 0.007.70%]; 99.0% [range 81.0-100%] vs. 98.0% [range 87.0100 %]; P <0.001 in all cases). The median of mononuclear MFI was also significantly decreased after transplantation (313.5 [range 70.0666.0] vs. 198.0 [range 66.0-520.0], p <0.001). However, CD4 + DR + / CD4 + and CD8 + DR + / CD8 + T cells were not significantly different after transplantation.
< Example 3> Correlation between immune cell ratio and clinical features after renal transplantation
The relationship between immune cell ratio after renal transplantation and clinical characteristics of renal transplant recipients was evaluated.
The baseline clinical characteristics of the patients are summarized in Table 2 . Gender, age, donor type, HLA incompatibility, and immunosuppressive factors did not significantly affect the ratio of T lymphocyte subpopulations to HLA-DR + mononuclear cells ( Table 3 ).
< Example 4> Immune cell ratio after renal transplantation CMV Correlation between infections
We compared the ratio of immune cells between patients with and without CMV infection after renal transplantation.
Five patients were infected with CMV after renal transplantation ( Table 4 ). Of these, three were diagnosed with CMV colitis, one with CMV gastritis, and one with CMV pneumonia. Before transplantation, all transplant recipients and donor serostatus were positive for anti-CMV immunoglobulin G. Patients infected with ganciclovir were given intravenously for a median of 15 days [range 5-30]. There was no significant difference in the ratio of T-lymphocytes to HLA-DR + mononuclear cells between kidney transplant patients and CMV-infected
≪ Example 5 & gt ; Correlation between immune cell ratio and acute rejection after renal transplantation
We compared the ratio of immune cells between patients who had acute rejection after renal transplantation and those who did not.
In the follow-up period, 12 patients were diagnosed with acute cellular rejection, 4 were diagnosed with CNI toxicity, and 5 were diagnosed with no specific pathology ( Table 1) ). The median creatinine level of the renal transplant recipients diagnosed with acute rejection was 3.06 mg / dL [range 1.71-8.50]. There was no significant difference in the clinical characteristics between patients with acute rejection and those without acute rejection. On the other hand, the proportion of CD4 + CD25 + / CD4 + T cells in patients with acute rejection was significantly increased compared with patients who were 2 weeks after renal transplantation ( Table 5 , 9.10% [range 4.3025.6 %] vs. 5.10% [range 0.10-33.3%]; p = 0.024). In addition, the proportion of CD4 + CD25 + / CD4 + T cells in renal transplant recipients with acute rejection was significantly increased (3.95% [range 1.80-5.60%] compared with patients with CNI toxicity or no specific pathology, ] And 3.80% [range 1.605.60%]; p = 0.045 and p = 0.006).
All patients who had acute rejection received steroid pulse therapy except for one patient who received thymoglobulin antibody treatment because of the lack of steroid therapy. The proportion of CD4 + CD25 + / CD4 + T cells in patients who had been treated with steroid pulse therapy for 2 weeks was lower than that at the time of acute rejection, but there was no statistical significance ( Table 5 , 7.4% [range 1.80-12.2%] vs. 9.10% [range 4.30-25.6%], p = 0.320). There were 9 patients with grade 1A of acute cellular rejection in Banff grade, 1 patient in
< Example 6> CD4 + CD25 + / CD4 + T cell of ROC analysis
The effect of CD4 + CD25 + / CD4 + T cell ratio in peripheral blood on the prediction of acute renal transplant rejection was analyzed by ROC curve analysis.
In the ROC curve analysis, it was judged that the cutoff of CD4 + CD25 + / CD4 + T cell ratio was 4.8%, and the acute rejection could be predicted with a sensitivity of 75% and an accuracy of 43.0% ( FIG. 2A ). ROC analysis of confounding variables showed a similar degree of predictability, with cutoff of CD4 + CD25 + / Cd4 + T cell ratio of 5.8% and sensitivity of 75% and accuracy of 68.4% ( Fig. 2B ). The area under the curve before and after adjusting the confounding variables were calculated to be 0.704 and 0.764, respectively, indicating that the ratio of CD4 + CD25 + / CD4 + T cells is a predictor of acute rejection.
As described above, the present invention provides a method and a composition for diagnosing acute rejection by measuring the ratio of CD4 + CD25 + T cells among all the CD4 + T cells present in the peripheral blood of kidney transplant patients. INDUSTRIAL APPLICABILITY The present invention can be effectively used to develop diagnostic reagents capable of effectively diagnosing acute renal transplant rejection.
Claims (8)
(a) collecting a blood sample from a kidney transplant patient;
(b) determining the ratio of CD4 + CD25 + T cells among CD4 + T cells present in the blood (CD4 + CD25 + T / CD4 + T cell); And
(c) determining that a rejection reaction is present when the ratio of T cells in the identified kidney transplant patient is increased as compared to the control.
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