anti-MICA Antibodies Research Articles

410.3: Anti-MICA antibodies and graft outcomes in kidney transplant recipients.

410.3: Anti-MICA antibodies and graft outcomes in kidney transplant recipients.

The impact of ageing on the distribution of preformed anti-HLA and anti-MICA antibody specificities in recipients from eastern China prior to initial HSCT

BackgroundWith the development of Hematopoietic Stem Cell Transplantation (HSCT) technology, increasing numbers of elderly patients were undergoing allogeneic HSCT and elderly patients with hematologic malignancies could benefit most from it. Preformed donor-specific human leukocyte antigen (HLA) antibodies (DSA) were associated with graft failure in HLA-mismatched allogeneic HSCT and the absence of DSA was the main criterion of selecting the donor. Except for sensitization events such as transfusion, pregnancy or previous transplantation, ageing affects the humoral immune response both quantitatively and qualitatively. To evaluate the prevalence and distribution of anti-HLA and antibodies of MHC class I chain related antigens A (MICA) specificities in different age groups before initial HSCT would provide HLA and MICA specific antibody profiles under the impact of ageing, which could provide meaningful information in the process of selecting suitable HLA-mismatched donors by avoiding preformed DSA.ResultsThere were no significant differences in the distribution of anti-HLA class I, class II and anti-MICA antibodies among the three age groups in this study except that a significant lower negative ratio of anti-HLA class I, class II antibodies and higher positive rate of MICA antibodies with maximum mean fluorescent intensity (MFI) > 5000 in the elderly than in young age group. The distribution of antibody specificities against HLA -A, -B, -C, -DR, -DQ, -DP and MICA antigens in the three age groups were generally consistent. The anti-HLA class I antibody specificities with higher frequencies were A80,A68;B76,B45;Cw17, which were unlikely to become DSA in Chinese. Anti-HLA class II antibody specificities were more likely to become potential DSA than class I.DR7, DR9, DQ7, DQ8 and DQ9 were most likely to become potential DSA.ConclusionsThe prevalence of anti-HLA and anti-MICA antibodies increased slightly as age increased. While ageing had a small impact on the distribution of antibody specificity frequencies against HLA-A, -B, -C, -DR,-DQ, -DP and MICA antigens in recipients awaiting initial HSCT from East China. The risk of developing preformed DSA was basically consistent in the three age groups and the elderly group might be more favorable in HLA-mismatched HSCT due to higher positive rate of anti-MICA antibody.

High maternal-fetal HLA eplet compatibility is associated with severe manifestation of preeclampsia.

Preeclampsia is responsible for more than 70 000 and 500 000 maternal and fetal deaths, respectively each year. Incomplete remodelling of the spiral arteries in placenta is the most accepted theory of preeclampsia pathogenesis. However, the process is complexed with immunological background, as pregnancy resembles allograft transplantation. Fetus expresses human leukocyte antigens (HLA) inherited from both parents, thus is semiallogeneic to the maternal immune system. Therefore, induction of fetal tolerance is crucial for physiological outcome of pregnancy. Noteworthy, the immunogenicity of discordant HLA antigens is determined by functional epitopes called eplets, which are continuous and discontinuous short sequences of amino acids. This way various HLA molecules may express the same eplet and some HLA incompatibilities can be more immunogenic due to different eplet combination. Therefore, we hypothesized that maternal- fetal HLA incompatibility may be involved in the pathogenesis of gestational hypertension and its progression to preeclampsia. We also aimed to test if particular maternal-fetal eplet mismatches are more prone for induction of anti- fetal HLA antibodies in gestational hypertension and preeclampsia. High resolution next-generation sequencing of HLA-A, -B, -C, -DQB1 and -DRB1 antigens was performed in mothers and children from physiological pregnancies (12 pairs) and from pregnancies complicated with gestational hypertension (22 pairs) and preeclampsia (27 pairs). In the next step HLA eplet identification and analysis of HLA eplet incompatibilities was performed with in silico approach HLAMatchmaker algorithm. Simultaneously maternal sera were screened for anti-fetal HLA class I, class II and anti-MICA antibodies with Luminex, and data were analyzed with HLA-Fusion software. We observed that high HLA-C, -B, and DQB1 maternal-fetal eplet compatibility was associated with severe preeclampsia (PE) manifestation. Both quantity and quality of HLA epletmismatches affected the severity of PE. Mismatches in HLA-B eplets: 65QIA+76ESN, 70IAO, 180E, HLA-C eplets: 193PL3, 267QE, and HLA-DRB1 eplet: 16Y were associated with a mild outcome of preeclampsia if the complication occurred. High HLA-C, HLA-DQB1 and HLA-B eplet compatibility between mother and child is associated with severe manifestation of preeclampsia. Both quantity and quality of maternal-fetal HLA eplet mismatches affects severity of preeclampsia.

Posttransplant-Alloantibodies Against MICA Antigens Associated With Decreased Long-Term Allograft Survival of Kidney Transplant Recipients

Previous evidence showed that antibodies against major histocompatibility complex class I-related chain A (MICA) could lead to antibody-mediated rejection in kidney transplantation in case where the patients had no alloantibodies against HLA. However, the effects of posttransplant anti-MICA antibodies on long-term renal allograft survival and function remained unsettled. We tested the posttransplant anti-MICA antibodies in 150 kidney transplant patients. The aim of this study was to compare the long-term graft survival and function between patients who were MICA positive and those who were negative. The posttransplant serum samples from 150 patients receiving kidney transplantation in our center from 2012 to 2013 were tested for MICA antibodies and HLA antibodies by Luminex single antigen array technology. Graft survival and function were followed up for a mean time of 74.2 months. The research was conducted in accordance with the Helsinki Congress and the Declaration of Istanbul. Of the 150 patients, 38 (25.3%) were sensitized against MICA after transplantation. The anti-MICA antibodies-positive (anti-MICA+) group had a worse long-term renal allograft survival than that of anti-MICA-negative (anti-MICA-) group (P = .029), even when stratified by posttransplant HLA sensitization status or donor source. Anti-MICA antibodies also had a detrimental impact on renal allograft function, but only at 1 year posttransplantation (estimated glomerular filtration rates at 1 year: anti-MICA+ 66.6 mL/min/1.73 m2 vs anti-MICA- 78.7 mL/min/1.73 m2; P = .023). Posttransplant anti-MICA antibodies were associated with decreased long-term renal allograft survival and short-term renal allograft function.

The MHC class I MICA gene is a histocompatibility antigen in kidney transplantation

The identity of histocompatibility loci, besides human leukocyte antigen (HLA), remains elusive. The major histocompatibility complex (MHC) class I MICA gene is a candidate histocompatibility locus. Here, we investigate its role in a French multicenter cohort of 1,356 kidney transplants. MICA mismatches were associated with decreased graft survival (hazard ratio (HR), 2.12; 95% confidence interval (CI): 1.45–3.11; P < 0.001). Both before and after transplantation anti-MICA donor-specific antibodies (DSA) were strongly associated with increased antibody-mediated rejection (ABMR) (HR, 3.79; 95% CI: 1.94–7.39; P < 0.001; HR, 9.92; 95% CI: 7.43–13.20; P < 0.001, respectively). This effect was synergetic with that of anti-HLA DSA before and after transplantation (HR, 25.68; 95% CI: 3.31–199.41; P = 0.002; HR, 82.67; 95% CI: 33.67–202.97; P < 0.001, respectively). De novo-developed anti-MICA DSA were the most harmful because they were also associated with reduced graft survival (HR, 1.29; 95% CI: 1.05–1.58; P = 0.014). Finally, the damaging effect of anti-MICA DSA on graft survival was confirmed in an independent cohort of 168 patients with ABMR (HR, 1.71; 95% CI: 1.02–2.86; P = 0.041). In conclusion, assessment of MICA matching and immunization for the identification of patients at high risk for transplant rejection and loss is warranted.

Targeting MICA/B with cytotoxic therapeutic antibodies leads to tumor control.

BackgroundMICA and MICB are tightly regulated stress-induced proteins that trigger the immune system by binding to the activating receptor NKG2D on cytotoxic lymphocytes. MICA and MICB are highly polymorphic molecules with prevalent expression on several types of solid tumors and limited expression in normal/healthy tissues, making them attractive targets for therapeutic intervention.MethodsWe have generated a series of anti-MICA and MICB cross-reactive antibodies with the unique feature of binding to the most prevalent isoforms of both these molecules.ResultsThe anti-MICA and MICB antibody MICAB1, a human IgG1 Fc-engineered monoclonal antibody (mAb), displayed potent antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) of MICA/B-expressing tumor cells in vitro. However, it showed insufficient efficiency against solid tumors in vivo, which prompted the development of antibody-drug conjugates (ADC). Indeed, optimal tumor control was achieved with MICAB1-ADC format in several solid tumor models, including patient-derived xenografts (PDX) and carcinogen-induced tumors in immunocompetent MICAgen transgenic mice.ConclusionsThese data indicate that MICA and MICB are promising targets for cytotoxic immunotherapy.

Targeting MICA/B with cytotoxic therapeutic antibodies leads to tumor control

Background: MICA and MICB are tightly regulated stress-induced proteins that trigger the immune system by binding to the activating receptor NKG2D on cytotoxic lymphocytes. MICA and MICB are highly polymorphic molecules with prevalent expression on several types of solid tumors and limited expression in normal/healthy tissues, making them attractive targets for therapeutic intervention. Methods: We have generated a series of anti-MICA and MICB cross-reactive antibodies with the unique feature of binding to the most prevalent isoforms of both these molecules. Results: The anti-MICA and MICB antibody MICAB1, a human IgG1 Fc-engineered monoclonal antibody (mAb), displayed potent antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) of MICA/B-expressing tumor cells in vitro. However, it showed insufficient efficiency against solid tumors in vivo, which prompted the development of antibody-drug conjugates (ADC). Indeed, optimal tumor control was achieved with MICAB1-ADC format in several solid tumor models, including patient-derived xenografts (PDX) and carcinogen-induced tumors in immunocompetent MICAgen transgenic mice. Conclusions: These data indicate that MICA and MICB are promising targets for cytotoxic immunotherapy.

Establishment of HLA class I and MICA/B null HEK-293T panel expressing single MICA alleles to detect anti-MICA antibodies

Pre- and post-transplantation anti-MICA antibody detection development are associated with an increased rejection risk and low graft survival. We previously generated HLA class I null HEK-293T using CRISPR/Cas9, while MICA and MICB genes were removed in this study. A panel of 11 cell lines expressing single MICA alleles was established. Anti-MICA antibody in the sera of kidney transplant patients was determined using flow cytometric method (FCM) and the Luminex method. In the 44 positive sera, the maximum FCM value was 2879 MFI compared to 28,135 MFI of Luminex method. Eleven sera (25%) were determined as positive by FCM and 32 sera (72%) were positive by the Luminex method. The sum of total MICA antigens, MICA*002, *004, *009, *019, and *027 correlation showed a statistically significant between the two methods (P = 0.0412, P = 0.0476, P = 0.0019, P = 0.0098, P = 0.0467, and P = 0.0049). These results demonstrated that HEK-293T-based engineered cell lines expressing single MICA alleles were suitable for measuring specific antibodies against MICA antigens in the sera of transplant patients. Studies of antibodies to MICA antigens may help to understand responses in vivo and increase clinical relevance at the cellular level such as complement-dependent cytotoxicity.

Clinical relevance of major histocompatibility complex class I chain-related molecule A (MICA) antibodies in live donor renal transplantation - Indian Experience.

Antibody-mediated rejections (AMR) in the absence of circulating anti-HLA-DSA have highlighted the role of non-HLA antibodies, particularly those directed against endothelial cells. Of these, MICA (major histocompatibility complex class I chain-related molecule A) antibodies are the most notable and important because of their potential in promoting graft rejections. Limited studies have focused on the impact of MICA donor-specific antibodies (DSA) on graft outcome as compared to those that are not donor-specific (NDSA). We evaluated pre- and post-transplant sera at POD 7, 30, 90, 180 and the time of biopsy from 206 consecutive primary live donor renal transplant recipients for anti-MICA and anti-HLA antibodies using single antigen bead assay on a Luminex platform. Recipients who developed MICA antibodies and their donors were phenotyped for MICA alleles. For the purpose of antibody analysis, patients were categorized into three major groups: biopsy-proven AMR, acute cellular rejection (ACR) and those with no rejection episodes (NRE). During the mean follow-up period of 17.37±6.88months, 16 of the 206 recipients developed AMR, while ACR was observed in only 13 cases. A quarter (25%) of the AMR cases had anti-MICA antibodies as compared to 7.7% of those experiencing ACR and 6.2% of the NRE group. Allelic typing revealed that all MICA Ab +ve AMR cases were due to the presence of donor-specific antibodies. MICA-DSA even in the absence of HLA-DSA was significantly associated with AMR but not with ACR when compared with the NRE group (P=<.01).

Importance des anticorps dans la prise en charge de la greffe de cellules souches hématopoïétiques : anticorps anti-HLA, anti-plaquettes, anti-granuleux, anti-érythrocytes et anti-MICA. Recommandations de la Société francophone de greffe de moelle et de thérapie cellulaire (SFGM-TC)

The presence of allo-antibodies in the serum of a recipient awaiting hematopoietic stem cell transplantation (HSCT) may have an impact on transfusion efficiency and/or donor choice, especially in the absence of an identical sibling donor. Prior to transplantation, donor specific anti-HLA (Human Leukocyte Antigen) antibodies (DSA) have a recognized effect on transplant outcome, correlated with the increasing MFI value and with the ability of such antibody to fix the complement fraction. Anti-platelet antibodies (anti-HLA class I and anti-HPA [Human Platelet Antigen]) are better involved in transfusion inefficiency and can be responsible for refractory status. ABO incompatibilities require a specific treatment of the graft in presence of high titer to avoid hemolytic adverse effects. Investigations of these antibodies should be carried out on a regular basis in order to establish appropriate transfusion recommendation, select an alternative donor when possible or adapt the source of cells. After transplantation, in case of delayed recovery or graft rejection, long term aplasia, persistent mixed chimerism or late release, and after elimination of the main clinical causes, a biological assessment targeted on the different type of antibodies will have to be performed in order to orient towards the cause or the appropriate therapy. Further studies should be carried out to determine the impact of anti-MICA antibodies and recipient specific anti-HLA antibodies, on the outcome of the transplantation.

Restoration of antitumor immunity through anti-MICA antibodies elicited with a chimeric protein

BackgroundNatural killer and cytotoxic CD8+ T cells are major players during antitumor immunity. They express NKG2D, an activating receptor that promotes tumor elimination through recognition of the MHC class I...

Soluble MICA and anti-MICA Antibodies as Biomarkers of Nasopharyngeal Carcinoma Disease

ABSTRACT The MHC class I chain-related molecule A (MICA) is a ligand for the activating natural killer (NK) cell receptor NKG2D. A part from its genetic diversity, MICA is characterized by the presence of membrane-bound and soluble isoform (sMICA) and by the propensity to elicit antibody-mediated allogeneicity (MICA Abs). Altogether such properties are important in the cancer setting. Here, we investigated whether MICA polymorphism, serum level of sMICA and MICA antibodies (Abs) may influence nasopharyngeal carcinoma (NPC) risk. 274 NPC naïve of treatment patients and 275 healthy individuals, all originating from Tunisia were included and genotyped. Among them, 160 sera from patients and 51 from controls were analyzed for the sMICA level by ELISA and were tested for the presence of MICA Abs by Luminex assay. The statistical analysis showed that: (1) we extend and confer our previous finding concerning Val/Val association with risk of NPC (p = .02, OR = 1.56; 95%CI [1.12–2.11]). (2) The higher level of sMICA characterized patients advanced stage of the disease. (3) The 18 (78%) of patients having MICA Abs exhibit all a non-advanced stage of the tumor extension at presentation. MICA129 Met /Val, sMICA and MICA Abs could be potential biomarkers of prediction, the diverse staging of NPC and hence prognostic and treatment.

MICA immune complex formed with alpha 3 domain-specific antibody activates human NK cells in a Fc-dependent manner

BackgroundOne of the mechanisms by which tumors evade immune surveillance is through shedding of the major histocompatibility complex (MHC) class I chain-related protein A and B (MICA/B) from their cell surface. MICA/B are ligands for the activating receptor NKG2D on NK and CD8 T cells. This shedding reduces cell surface levels of MICA/B and impairs NKG2D recognition. Shed MICA/B can also mask NKG2D receptor and is thought to induce NKG2D internalization, further compromising immune surveillance by NK cells.MethodsWe isolated human primary NK cells from normal donors and tested the suppressive activity of soluble recombinant MICA in vitro. Utilizing a panel of novel anti-MICA antibodies, we further examined the stimulatory activities of anti-MICA antibodies that reversed the suppressive effects of soluble MICA.ResultsWe show that suppressive effects of soluble MICA (sMICA) on NK cell cytolytic activity was not due to the down-regulation of cell surface NKG2D. In the presence of an α3 domain-specific MICA antibody, which did not obstruct NKG2D binding, sMICA-mediated NK cell suppression was completely reversed. Reversal of NK cell inhibition by sMICA was mediated by immune complex formation that agonized NKG2D signaling. Furthermore, this restorative activity was dependent on antibody Fc effector function as the introduction of Fc mutations to abrogate Fc receptor binding failed to reverse sMICA-mediated NK cell suppression. Furthermore, MICA immune complexes preformed with an α3 domain-specific antibody (containing a wild-type Fc) induced IFN-γ and TNF-α secretion by NK cells in the absence of cancer cells, whereas MICA immune complexes preformed with the Fc effectorless antibody failed to induce IFN-γ and TNF-α secretion. Finally, we demonstrated that MICA immune complexes formed with the α3 domain-specific antibody activates NKG2D on NK cells leading to the release of IFN-γ.ConclusionsOur results demonstrate that an α3 domain-specific MICA antibody can circumvent sMICA-mediated suppression of NK cell cytolytic activity. Moreover, our data suggest that MICA immune complexes formed with α3-specific antibodies can activate NKG2D receptor and restore NK cell function in a Fc-dependent manner. The clinical utility of α3 domain-specific MICA/B antibodies may hold great promise as a new strategy for cancer immunotherapy.

Anti MICA Antibody (major histocompatibility complex class I related Chain A) Whether to Treat or Avoid?

Aims To study the role of MICA antibody in living renal transplantation in the absence of anti HLA antibodies. Methods A retrospective study of patients undergone living renal transplantation between 2000-2014 was performed. Recipients were classified in two groups, pre transplantation Anti MICA antibody positive group (n=17) and antibody negative comparison group (n=17). Patients with anti HLA antibodies were excluded and only isolated MICA positive patients were included in the study group. All recipients undergone tolerance protocol and post transplant T-regulatory cells, and were comparable in recipient age, donor age, donor relation, HLA and immunosuppression including induction. Results Patients with pre transplant MICA antibody positivity were associated with increased acute rejection as compared to comparison group (47% vs 11.7 %, p value= 0.02 ). Renal function in MICA positive group and comparison group were comparable over a mean follow up of 6.5 years (mean s.creatinine 1.58 vs 1.53 mg/dl ). Rate of chronic rejection was same in both groups (5.8% ). No patient or graft loss in either group over mean follow up of 6.5 years. Conclusion Isolated Anti MICA antibody positivity is uncommon event. Pre transplant anti MICA antibody positivity is associated with increased acute rejection rates. However chronic rejection rates and renal function are comparable in both groups. Thus our study emphasizes that MICA antibody positive patients may require more aggressive immunosuppression, role of desensitization has to be defined.

Non-HLA Antibodies in Highly Sensitized Renal Transplant Candidates.

Introduction Non-HLA allo- and autoantibodies, as are antibodies (abs) against Major-histocompatibility-complex class I–related-chain A (anti-MICA) and angiotensin II type 1 receptor (anti-AT1R), are implicated in rejection and graft failure post renal transplantation. These abs are not detected with the classical crossmatch before transplantation. The aim of this study was to assess the incidence of preformed anti-MICA and anti-AT1R abs in highly sensitized renal transplant candidates (HSP, with %cPRAs>70) as compared to non sensitized patients (%cPRAs<5) awaiting for renal transplantation, in order to define possible additional pre-transplant immunological risk factors. Materials and Methods In total, 169 renal transplant candidates were tested, including 115 HSP (study group) and 54 non-sensitized patients (control group-CG-pts). Anti- HLA sensitization in HSP vs CG-pts was due to previous transplantation(s) (81 vs 0 pts), pregnancies (25 vs 6 pts) and transfusions (82 vs 10 pts). Blood samples were tested (a) for anti-HLA and anti-MICA antibody specificities by Single Antigen Bead Assay (Luminex, One Lambda) and (b) for AT1R-abs by ELISA (EIA-AT1R kit, One Lambda). For anti-HLA and anti-MICA abs an MFI >1000 was considered as positive. Anti-AT1R-ab levels were classified as low <10U/mL, at risk 10-17U/mL and high>17U/mL. The Chi Square test (Yate’s corrected) was used for statistical analysis. Results and Discussion Broad sensitization against HLA alleles was observed in HSP with 93/115 HSP to exhibit abs against both HLA class I & II loci. More precisely, antibodies against HLA-A,-B,-C,-DRB1,-DQA1,-DQB1,-DPB1 was observed in 83%, 85%, 58%, 82%, 32%, 73% and 32% of the HSP respectively. Anti-MICA-abs were detected in 17/115 (14,8%) HSP and in 1/54 (1.8%) CG-pts (p=0.02). Anti-AT1R-abs were detected in 44/115 (38,3%) HSP and 5/54 (9.2%) CG-pts (p=0.0002). The anti-AT1R-abs were detected either in intermediate (n=32, 27,8%) or high levels (n=12, 10,4%) in HSP with mean±SD values of 12.3±1.9 and 25.4±10.5 U/ml respectively. The anti-AT1R-ab levels in 4 positive CG-pts were close to cut-off with mean±SD values 11.2±1.5 U/ml while only one patient presented high levels. The presence of anti-AT1R-abs was associated with pregnancies and/or graft loss. All HSP with only transfusion history had low anti-AT1R levels. The presence of anti-MICA-abs was significantly correlated with anti-AT1R-abs (p=0.01). Conclusion Given the complexity of mechanisms involved in kidney graft rejection, HLA as well as non-HLA pre transplant antibody responses should be taken into account in order to define patients with particular risk for irreversible graft injury. Highly sensitized renal transplant candidates have additional to donor HLA risk factors before renal transplantation. Detection of non-HLA antibodies may be useful in immunological risk assessment pre-transplantation and may help clinicians to establish therapeutic protocols in order to improve graft outcome.

Role of Anti-MICA Antibodies in Graft Survival of Renal Transplant Recipients of India.

Introduction The MIC (MHC class I chain-related) genes are a group of nonclassical MHC genes, located in the MHC class 1 region of chromosome 6. The aim of the present study was to find the prevalence of MHC class 1 chain-related (MICA) alloantibodies in patients undergoing live-related donor renal transplantation and its role in short-term graft survival. The role of blood transfusion in the formation of these antibodies was also studied. Materials and Methods Pretransplant samples of patients undergoing renal allograft transplantation were tested for anti-MICA antibodies. Association of various demographics, HLA-A + B + DRB1 mismatches, anti-HLA antibody screen, and anti-MICA antibodies was assessed using Pearson's chi-square test. Results Out of 646 serum samples, 94 (14.6%) were positive and 552 (85.4%) were negative for anti-MICA antibodies. Patients with anti-MICA antibody had a graft survival 89.3% as compared to 94.7% in patients without anti-MICA antibody (P < 0.05). The hazard ratio for all patients was 3.0701 (P < 0.05). Out of the 340 patients with no HLA antibodies, the presence of anti-MICA antibodies without any HLA antibodies (n = 43) was associated with poor outcome in the patients (hazard ratio of 2.768, P < 0.05). The presence of MICA antibodies with HLA antibodies did not decrease the graft survival (hazards ratio of 1.3750, P > 0.05). Conclusion Preformed MICA antibodies independently increase the risk of kidney rejection and therefore recommend that guidelines should be formed for mandatory testing of these antibodies prior to renal transplant.

The incidence and clinical relevance of anti-HLA and/or MICA antibodies in patients with long-term survival renal allo-grafts

The purpose of this study was to analyze the incidence and clinical relevance of anti-HLA and/or MICA antibodies in renal allo-grafts transplant recipients with long-term renal survival (> 5 years). This retrospective study collected post-transplant serum samples from a total of 110 patients which were used to detect the incidence of anti-HLA and/or MICA antibodies as well as anti-HLA donor specific antibodies. Among these 110 patients, 72 patients had antibodies against HLA and/or MICA at the time of test, 61 had only anti-HLA antibodies, 31 had anti-MICA antibodies, and 38 were antibody negative. There was no difference in the number of patients developing antibodies against non-donor specific antibodies, donor specific antibodies, Class I donor specific antibodies, Class II donor specific antibodies or MICA antibodies between normal function group (serum creatinine level < 2.0 mg/dL) and dysfunction group (serum creatinine level > 2.0 mg/dL). For the serum creatinine level, estimated glomerular filtration rate and blood urea nitrogen level, patients with different antibodies were not statistically different to antibody-negative patients. Cox regression analysis showed that the type of transplantation and HLA mismatch number were significant negative risk factors for the development of anti-HLA (P < 0.05). Our results suggested that the anti-HLA antibody status has little impact on the renal graft function in the long-term survival allo-graft renal recipients.

P164 Role of anti-mica antibodies in graft survival of renal transplant recipients of India: A single centre experience

Aim To find the incidence of MHC class I chain-related chain A (MICA) alloantibodies in patients undergoing live related donor (LRD) renal transplantation and their association with short-term graft survival. Methods Pre-transplant, consecutive, serum samples of ESRD patients undergoing first renal allograft transplantation were tested for anti-MICA antibodies. Association of various demographics, HLA-A + B + DRB1 mismatches and HLA antibody screen with MICA antibodies was assessed using Pearson’s Chi-square test. A multivariate analysis was also performed to check for potential confounders. The effect of pre-transplant blood transfusions on antibodies against HLA Class 1 & class II, or MICA was studied. Results Out of 646 serum samples for MICA antibodies, 94 (14.6%) were positive and 552(85.4%) negative for MICA antibodies. Patients with MICA antibody had a graft survival 89.3% as compared to 94.7% in patients without MICA antibody (P = 0.01). The hazards ratio for all patients was 3.744 (P = 0.01). MANOVA effect was determined for three factors (HLA antibody, MICA antibody & HLA mismatch) and Graft survival which was statistically significant. Two of the three ANOVA’s were statistically significant viz. MICA antibody and presence of HLA antibody. Conclusions MICA antibodies were present in 14.6% of the patients. Preformed MICA antibodies independently increase the risk of kidney rejection and therefore a guideline should be made for mandatory testing of these antibodies prior to transplant.

Anti MICA (Major Histocompatibility Complex Class I) Related Antibody, Whether to Treat or Avoid in Renal Transplantation?

Introduction Pre-transplantation anti-major histocompatibility complex class-I related chain A (MICA) sensitization is an uncommon event and its role in kidney graft evolution is not completely defined. • Even when kidney allografts are well matched for HLA as in living related transplant and antiHLA antibodies are not detected, graft rejection can still occur. • Anti MICA antibody is reportedly associated with poor transplant outcomes and a high risk of acute and chronic rejection in renal transplantation. Methods A retrospective study of patients undergone living renal transplantation between years 2000-2014 was performed. • Recipients were classified in two groups, pre-transplantation Anti MICA antibody positive group (n=17) and antibody negative comparison group (n=17). • Patients with anti HLA antibodies were excluded and only isolated MICA positive patients were included in the study group. • Both groups were comparable in recipient age, donor age, donor relation, HLA and immunosuppression. Results Patients with pre transplant MICA antibody positivity were associated with increased acute rejection rate as compared to comparison group (47% vs. 11.7 %, p value= 0.02). • Renal function in MICA positive group and comparison group were comparable over a mean follow up of 6.5 years (mean creatinine 1.58 vs. 1.53 mg/dl). Rate of chronic rejection was same in both groups (5.8%). • No patient loss or graft loss occurred in either group over mean follow up of 6.5 years. Conclusion IsolatedAnti MICA antibody positivity is uncommon event. • Pre transplant anti MICA antibody positivity is associated with increased acute rejection rates. However chronic rejection rates and renal function are comparable in both groups. • Thus our study emphasizes that MICA antibody positive patients may require more aggressive immunosuppression. Role of desensitization has to be defined.

Immune biomarkers and long‑term graft survival: a prospective follow‑up of 457 kidney transplant recipients.

INTRODUCTION Antibodies against donor human leukocyte antigens (HLAs) play a significant role in the pathogenesis of antibody‑mediated rejection, although their relevance during the late posttransplant period is unknown. A non‑HLA polymorphic antigenic system, like major histocompatibility class I chain‑related antigen A (MICA), might be another target for antibody responses involved in rejection. OBJECTIVES We conducted a 7‑year prospective study to determine the effect of positivity for anti‑HLA and anti‑MICA antibodies on kidney graft survival. PATIENTS AND METHODS A random blood sample was collected from 457 kidney recipients during a regular outpatient visit. Patients who were less than 6 months after transplantation were excluded. Evaluation of anti‑HLA (classes I and II) and anti-MICA antibodies was performed with the use of Luminex assays. An outpatient registry was used to monitor kidney function during a 7‑year follow‑up. RESULTS A total of 147 patients (32%) had anti‑HLA and 88 patients (19%) had anti‑MICA antibodies. Graft failure occurred in 67 anti‑HLA‑positive individuals (46%) as compared to 81 anti‑HLA‑negative ones (26%) (P <0.05), and in 30 anti‑MICA‑positive individuals (34%) as compared to 118 anti‑MICA‑negative ones (32%) (P = 0.52). Anti‑HLA antibodies were associated with increased incidence of graft failure: it was reported in 200 patients with an estimated glomerular filtration rate of more than 30 ml/min/1.73 m2 body surface area more than 5 years after transplantation (P <0.005). CONCLUSIONS Anti‑HLA, but not anti‑MICA, antibodies in randomly obtained blood samples were the significant predictor of late kidney graft failure and could be a low‑cost method enabling identification of patients requiring an individualized posttransplant approach. The results of our study provide an additional rationale for investigating immune biomarkers in certain diseases.