Donor-specific antibodies against HLA-C, HLA-DP and HLA-DQ and their implications in kidney transplantation

Table 1 Summaries of reported literature on HLA-C typing and anti-HLA-C donor-specific antibody

Ref.	Journal/year	Study type and sample size	Objectives	Findings
Albrechtsen et al[75]	Transplantation Proceedings/1977	Retrospective: 142 living related 311 cadaveric transplants	To study influence of HLA on the outcome of kidney transplantation	No beneficial of HLA-C matching was found
Bryan et al[6]	Clinical Transplantation/2010	Retrospective: 60 sensitized patients	To describe frequency of HLA class I DSA	There was 42% positivity to HLA-Cw, which was significantly lesser than sensitization to HLA-A (80%) and HLA-B (83%)
Duquesnoy and Marrari[29]	Transplant Immunology/2011	Retrospective: Sera from 45 HLA-C mismatch after allograft nephrectomy	To detect antibodies against HLA-C epitopes in patients with rejected kidney transplants	HLA-C antibody frequencies and reactivities were lower than those induced by donor HLA-A and HLA-B mismatches
Ling et al[5]	Human Immunology/2012	Prospective observational: 1069 patients on waiting list	To determine prevalence and the strength of anti-HLA-Cw and -DP and effect on clinical outcome	Low prevalence and the strength of anti-HLA-Cw and HLA-DP as compared to others and patient and graft survival was 100% without rejection
Frohn et al[79]	Nephrology, Dialysis, Transplantation/2001	Retrospective analysis of 104 pairs analysis for HLA-C matching	To analyze if acute graft rejection is influenced by HLA-C matching	After exclusion of linkage disequilibrium, HLA-C mismatch was significantly associated with rejection (P = 0.004)
Chapman et al[30]	Transplantation/1986	Case report	—	Case report of hyperacute rejection in renal allograft recipient having HLA-Cw5 antibody
Baan et al[32]	Transplantation/1993	Case report of rejection in an unsensitized recipient of deceased kidney	—	Rejection was reported in HLA-C mismatched along with sublocus HLA-Bw22
Bachelet et al[31]	American Journal of Transplantation /2011	Case report of AMR in patient with immunoglobulin A nephropathy undergoing 3rd transplant	—	Anti-HLA-Cw DSA led to positive flow cytometry crossmatch and irreversible acute AMR
Gilbert et al[80]	Transplantation Proceedings/2011	Retrospective analysis of immunized recipients, (n = 176) had antibodies against only classical HLA antigens (A, B, DR and DQ) and 13.3% (n = 27) antibodies against HLA-C and/or HLA-DP	To determine whether the presence of specific HLA-C and HLA-DP antibodies before transplantation influenced graft outcomes in immunized recipients	DSA against HLA-C and HLA-DP along with DSAs against HLA-A, -AB, -DR and -DQ led to significant increase in the number of acute rejection episodes and graft loss due to immunological reasons
Suneja and Kuppachi[33]	Clinical Kidney Journal/2012	Case report of 21-yr-old transplant recipient who developed AMR after 21 mo of transplantation	—	DSA against HLA-Cw17 led to AMR
Aubert et al[9]	American Journal of Transplantation /2014	Retrospective case–control study of 608 renal transplant patients	To evaluate the clinical relevance of the presence of anti-HLA-C DSA at d 0	Incidence of AMR was significantly higher (27.3%) in patients with anti-HLA-C DSA and median MFI was 4966, which was significantly higher in AMR group
Bosch et al[76]	Human Immunology/2014	Case report of AMR in the second transplant	—	Patient had low MFI < 1000 in 1st transplant and has HLA-C mismatched second kidney and developed AMR on d 7
Bachelet et al[10]	Transplantation/2016	Comparative retrospective analysis of 199 who were divided in three groups for comparison	To analyze clinical impact of HLA-Cw/DP DSA by comparing with HLA-sensitized kidney transplant recipients with no DSA at d 0 and recipient with recipients with preformed HLA-A, HLA-B, HLA-DR and HLA-DQ DSAs	Positive flow cross match, 2-yr biopsy proven rejection were more in HLA-Cw/DP DSA and preformed HLA-A, -B, -DR and -DQ DSAs as compared to group with no DSAs and similarly less graft survival in HLA-Cw/DP DSAs and preformed HLA-A, -B, -DR and -DQ DSAs as compared to no DSAs
Santos et al[34]	World Journal of Transplantation/2016	Retrospective cohort study: 12 patients with anti HLA-Cw DSA and 23 with anti-HLA-A or HLA-B	To analyze the clinical impact of preformed anti-HLA-Cw vs anti-HLA-A and/or HLA-B DSAs in kidney transplantation	Similar risk of AMR (P = 1) and impact on graft function (P = 0.528) as compared to anti-HLA-A and/or HLA-B DSA
Persaud et al[77]	Human Immunology/2017	Case report of AMR in a living related transplant	—	Sensitization to HLA-Bw6 via exposure to paternal HLA-C14 during pregnancy likely predisposed this patient to AMR
Abuzeineh et al[78]	Clinical Nephrology Case Studies/2020	Case report of AMR in 39 yr old unsensitized patients	—	De novo DSAs against HLA-C led to AMR. Unexplained Fabry-like zebra bodies were also seen in biopsy
Visentin et al[82]	American Journal of Transplantation /2020	Retrospective observational study of 135 patients	To compare the pathogenicity of preformed anti-denatured and anti-native HLA-Cw antibodies in kidney transplant recipient	Anti-native HLA DSA had more acute and chronic AMR (P = 0.006 and P = 0.03, respectively), and had lower graft survival (P = 0.04)
Laboux et al[81]	Transplant International/2023	Retrospective multicentral observational study of 183 patients	To determinate risk factors of AMR in recipients transplanted with preformed isolated Cw-DSA or DP-DSA	The 12% in the HLA-Cw-DSA group, vs 28% in the HLA-DP DSA group had AMR. The increased risk associated with HLA-DP DSA compared with HLA-Cw DSA, was significant only for MFI < 3000

AMR: Antibody-mediated rejection; DSA: Donor specific antibody; HLA: Human leukocyte antigen; MFI: Mean florescence intensity.

Table 2 Summaries of reported literature on HLA-DP typing and anti-HLA donor-specific antibody

Ref.	Journal/year	Study type and sample type	Objectives	Findings
Rosenberg et al[49]	Human Immunology/1992	Retrospective study of 37 patients	To study the influence isolated HLA-DP mismatches between donors and recipients	No benefit was found
Pfeiffer et al[48]	Transplant International/1995	Retrospective analysis of sera from 505 patients	To study the frequency and impact on graft function of HLA-DP antibodies	HLA-DP antibodies were found in 7.3%, and those with prior antibodies who had retransplantation had no impact on graft function
Redondo-Pachón et al[83]	Transplant Immunology/2016	Retrospective analysis of 440 kidney transplant patients	To study the effect of antibodies against HLA-DP detected with solid-phase assays on graft survival after kidney transplantation	No effect of survival was found
Mytilineos et al[95]	Transplantation/1997	Retrospective study in which 3600 retrospective DNA typing was performed first and then repeated in 1300 deceased kidney transplant	To assess influence of HLA-DPB mismatches on kidney graft outcome	No effect on 1st transplant. In 2nd transplant, the 1-yr survival rate of transplants with no HLA-DPB mismatch was 83% ± 2%, which was significantly higher than grafts with 1 mismatch (76% ± 2%, P = 0.02) and that of 2 mismatches (73% ± 3%, P = 0.003)
Laux et al[96]	Transplantation/2003	Retrospective analysis of 1478 patients who received a cadaver kidney retransplant	To study the effect of HLA-DPB1 epitopes on graft outcome	< 2 epitope mismatches have better survival than three epitope mismatches (at 2 yr: 77.8% vs 65.8%, P = 0.0112)
Qiu et al[97]	Transplantation/2005	Multicenter brief report of 232 sera from 4 centers	To describe the frequency of HLA-DP antibodies found in 323 patients who had functioning and rejected renal allografts	The 5.1% of 138 patients with functioning grafts, and 19.5% of 185 patients with rejected grafts (P < 0.001) had anti HLA-DP antibodies
Samaniego et al[87]	Clinical Transplants/2006	Case report of AMR due to HLA-DP DSA	—	Anti-HLA-DP antibody led to HLA-C4d-positive AMR
Vaidya et al[88]	Human Immunology/2007	Cas report of positive B cell crossmatch in full match patient	—	A single HLA-DP allele mismatch (DPB1 0601) resulted in positive B cells
Goral et al[89]	Nephrology, Dialysis, Transplantation/2008	2 case reports. 1st case was sensitized due to retransplant, pregnancy and blood transfusion and 2nd case was sensitized by blood transfusion only	—	Both cases has mixed rejections (acute cellular and AMR) needing therapy. First case has rejection in 2 mo and second case on d 12
Thaunat et al[90]	Transplant Immunology/2009	Case report of chronic AMR due to anti HLA-DP and antibodies to nondonor-specific HLA-DP, which has same amino acid sequence	—	Anti HLA-DP antibodies resulted in chronic AMR and author recommended epitope matching instead of antigen matching
Singh et al[91]	Transplantation/2010	Case report of fully matched patient who has 3 failed transplants and rejection due to anti-HLA-DP antibody	—	Patient develop borderline cellular rejection and AMR after 2 wk. There was a mismatch at the HLA-DPA1 locus and pre- and post-transplant sera identified DSA against DPA1 0103
Billen et al[98]	Tissue Antigens/2010	Retrospective analysis of pre- and post-transplant sera for HLA-DP antibodies	To analyze the incidence of HLA-DP antibodies in renal patients	The 14% (48/338) had anti HLA-DP DSAs. The 23% of these had DSAs pretransplant and 77 had DSAs after transplant. All DSAs had a single mismatch at a hypervariable region in 80% of cases
Jolly et al[85]	American Journal of Transplantation/2012	2 case reports. Case 1 was sensitized and had 3rd transplant with mismatches only for HLA-C 15 and HLA-DPB1 01 with negative crossmatch. Case 2 was live unrelated transplant from wife with 1-2-1 HLA-A, HLA-B, HLA-DR mismatched graft, with an additional single mismatch at the DP locus with positive B cell crossmatch	—	Patient 1 had acute cellular rejection on d 3 and AMR at wk 4. Patient 2 had AMR on d 11
Callender et al[7]	Human Immunology/2012	Retrospective analysis of 650 renal patients on waiting list	To determine the frequency of HLA-DP-specific antibodies in presence and absence of crossreactive HLA-DR antibodies	42% were reactive for HLA-DP antibodies. 58 of these were negative for crossreactive HLA-DR antigens, and 16 had no class II antibodies other than anti-HLA-DP
Mierzejewska et al[84]	Human Immunology/2014	Case report of recipient who had 3rd transplant and was completely matched except at HLA-DPA1 and -DPB1	—	AMR at d 13 due to presence of C1q binding IgG1 DSA against donor HLA-DPA1 and -DPB1
Cippà et al[50]	Human Immunology/2014	Case report of de novo donor HLA-DP-specific antibodies in a nonsensitized patient	—	Late AMR due to anti-HLA-DPS
Hörmann et al[99]	Clinical Transplantation/2016	Retrospective analysis of 195 consecutive kidney transplant patients	To study incidence and impact of anti-HLA-DP antibodies in renal transplantation	81 (49%) patients had anti-HLA-DP antibodies. Around 64% (n = 52) of patients were positive in the pretransplant samples and 36% (n = 29) were positive post-transplant. Anti-HLA-DP antibody-positive patients had a higher rate of rejection (P = 0.01)
Thammanichanond et al[92]	Transplantation Proceedings/2018	Case report of acute AMR by de novo Anti-HLA-DPβ and -DPα antibodies after kidney transplantation	—	Developed acute cellular and AMR after 15 months
Nikaein et al[93]	Transplant Immunology/2018	Brief communication of 2 cases who received transplants, 1 from living unrelated and the other from deceased donors. Both cases had DSAs to HLA-DPB with MFI > 15000	—	Both developed AMR (acute humoral rejection)
Marie et al[94]	Transplantation Report/2021	Case report of kidney transplants in 3 highly sensitized individuals with significant sensitization with donor-directed HLA-DP antibody and had kidney transplants from donors after brain death with positive B cell flow cytometry crossmatch	—	Case 1 (retransplant) had transplant glomerulopathy after 2 yr. Case 2 had no events. Case 3 had retransplant and AMR on d 10
Thammanichanond et al[86]	BMC Nephrology/2022	Case report of acute AMR associated with preformed HLA-DPα and HLA-DPβ DSAs that were not detected before transplantation	—	AMR at d 15 (this was first transplant)
Seitz et al[100]	Kidney International Reports/2022	Retrospective case–control study of 23 patients	To study the effect of pre-existing isolated HLA-DP-DSAs on renal allograft outcomes	Pre-existing HLA-DP DSAs was risk factor for AMR on multivariate analysis (HR = 9.578, P = 0.012). Patients with HLA-DP DSAs had increased microvascular scores (P = 0.0346) and worse transplant glomerulopathy (P = 0.015) compared with the standard immunological risk group
Pan et al[101]	HLA/2023	Meta-analysis of 5 studies with 1166 kidney transplant patients	To study the impact of preformed and de novo HLA-DP antibodies after renal transplantation on graft loss and rejection	De novo HLA-DP antibodies after transplantation showed an increased risk of graft loss or acute rejection (OR = 3.6, 95%CI: 1.6–8.10, P = 0.002, I2 = 52%). Preformed anti-HLA-DP antibodies did not show any effect

AMR: Antibody-mediated rejection; DSA: Donor specific antibody; HLA: Human leukocyte antigen.

Table 3 Summaries of reported literature on HLA-DQ typing and anti-HLA-DQ donor-specific antibody

Ref.	Journal/year	Study type and sample type	Objectives	Findings
Taylor et al[104]	Tissues Antigens/1987	Case report	—	B cell crossmatch positive due to IgG DSA against HLA-DQ did not affect graft function till 1 yr follow-up
Bushell et al[54]	Human Immunology/1989	Retrospective study of 25 HLA-DQ-mismatched but DR-matched patient	To study effect of HLA-DQ mismatch in HLA-DR-matched patients	No beneficial effect
Freedman et al[111]	Clinical Transplants/1997	Retrospective study of 12050 deceased 1st kidney transplant	To analyze the effect of HLA-DQ phenotype matching on renal allograft survival	Nonsignificant 3.0% reduction in graft failure (P = 0.38) was observed for each level of increasing HLA-DQ match when using the Cox regression model adjusted for recipient and donor race, age and sex, cold ischemia time, body mass index, cyclosporine A use, year of transplant, diabetes mellitus, HLA-A, HLA-B and HLA-DR match
Iniotaki-Theodoraki et al[108]	Transplantation/2003	Case–control study of 142 patients. Group A had 32 immediately post-transplant patients and group B had 110 sensitized patients who had failed grafts	To study humoral immune reactivity against HLA-DQ graft molecules in the early post transplantation period	No rejection or graft dysfunction in first 6 months
Duquesnoy and Marrari[29]	Transplant Immunology/2008	Retrospective analysis of 75 class-II-sensitized patients with different types of failed allografts including 60 kidney, 4 liver, 4 heart, 2 lung, 2 pancreas and 3 small bowel transplants	To describe the effect the donor-specific HLA class II epitope mismatching on antibody reactivity patterns	HLA-DQB and -DQA mismatches led to production of anti-HLA-DQB antibodies in 87% and HLA-DQA antibodies in 64%
Hartono et al[105]	Journal of Medical Case Reports/2009	Case report of a successful retransplant with pre-existing anti-HLA-DQ5 antibodies	—	Graft function good until 2 years without any deleterious effects
Tambur et al[110]	Transplantation/2010	Observational study of the sera of 104 patients	To identify HLA-DQ antibodies directed to patient’s own DQ or DQ chain linked to non-self DQ chains	7% of patients had anti -HLA-DQ antibodies against patient’s own DQ or DQ chain. 21% had antibodies to their own DQβ chain and 62% had antibodies to their own DQα chain
Kobayashi et al[109]	Human Immunology/2011	Observational study of 586 kidney transplant recipients	To know the impact of DSAs against HLA-DRB and -DQB on development of chronic AMR in high, moderate and low risk	Anti-HLA-DQB DSAs were not associated with chronic AMR in all immunological risk categories
Willicombe et al[56]	Transplantation/2012	Retrospective analysis of 505 kidney transplant recipients	The aim of this study was to establish the incidence and outcomes after the development of HLA-DQ DSAs	Patients with anti-HLA-DQ DSAs were at significant risk for AMR, transplant glomerulopathy, and allograft loss (P < 0.0001)
DeVos et al[57]	Kidney International/2012	Prospective analysis of retrospective data of 347 without pretransplant DSAs	To study development of de novo anti-HLA-DQ DSAs and its impact on patient and graft	78% of all DSAs were anti-HLA-DQ. No relation with rejection found. Mean creatinine and proteinuria higher in anti-HLA-DQ DSAs. Anti-HLA-DQ DSAs along with non-DQ DSAs led to reduced 3-yr survival
Freitas et al[115]	Transplantation/2013	Retrospective analysis of 284 transplant recipients	To study complement-binding characteristics of HLA-DQ DSAs	Anti-HLA-DQ DSAs and non-DQ DSAs caused more acute rejection (P = 0.0009), increased graft loss and reduced 5-yr survival. Acute rejection had more IgG1/IgG3 combination and C1q-binding antibodies (51%, P = 0.01; and 63%, P = 0.001)
Tambur et al[116]	Transplantation/2014	Clinical and translational research in 40 transplant recipients	To analyze eplet and epitope of HLA-DQ in immunologically naive patients before failed transplantation	10 HLA-DQA eplets or eplet combinations and 13 HLA-DQB eplets or combinations identified
Sapir-Pichhadze et al[112]	American Journal of Transplantation/2015	Case–control study of 156 kidney transplant recipients. Cases consisted of patients with transplant glomerulopathy and controls without transplant glomerulopathy	To assess risk of transplant glomerulopathy as a function of donor and recipient HLA-DR and HLA-DQ incompatibility at the eplet level	Logistic regression model showed increased odd of transplant glomerulopathy (OR = 2.84, 95%CI: 1.73-7.84) in 27-43 eplet mismatches and (OR = 4.62, 95%CI: 1.51-14.14)
Lim et al[74]	Clinical Journal of the American Society of Nephrology/2016	Retrospective observational data of 788 recipients followed for 2.2 years	To assess impact of HLA-DQ mismatches on rejection	Compared with 0 HLA-DQ mismatched kidneys, those who received 1 or 2 HLA-DQ mismatched had more rejections (P < 0.01), late rejections (P = 0.03), and AMR (P = 0.01)
Chowdhry et al[106]	Asian Journal of Transfusion Science/2019	Case report of de novo DSAs against HLA-DQ in a retransplant	—	Chronic AMR after 2 years
Liu et al[107]	Transplant Immunology/2022	Case report of DSA against HLA-DQA1	—	Mixed rejection after 2 years

AMR: Antibody-mediated rejection; DSA: Donor specific antibodies; HLA: Human leukocyte antigen; IgG: Immunoglobulin G; OR: Odds ratio.