Minor ABO Mismatch Research Articles

The influence of blood group differences in allogeneic hematopoietic peripheral blood progenitor cell transplantation

Severe immunohematologic complications after ABO-mismatched allogeneic blood peripheral blood progenitor cell (PBPC) transplantation (PBPCT), including pure red cell aplasia and immune hemolysis, have been described. Although several studies have addressed this issue, the clinical influence of blood group differences on transfusion requirements and survival is still discussed controversially, especially in the case of PBPCT. This single-center study is based on 143 patients receiving PBPCT after standard or reduced-intensity conditioning. The influence of blood group differences in the ABO, Rh, and Kell systems on red blood cell, platelet, and plasma transfusion requirements; length of hospitalization in transplantation unit; survival; and occurrence of graft-versus-host disease was investigated. Additionally, the influence of the conditioning regimen and irregular antibodies on the measures mentioned above was analyzed. Multivariate analysis demonstrated that minor and bidirectional ABO mismatch (p = 0.028) and Rh difference (p = 0.020) independently led to poorer survival. The Kell difference did not show significant influences on the measures mentioned above. A clinically relevant influence of blood group differences on transfusion requirements could not be demonstrated. Irregular antibodies also did not show significant influences. These findings indicate an influence of blood group differences in PBPCT on survival and must be studied in further detail.

A new concept of accommodation in ABO‐incompatible kidney transplantation

This work focuses on the mechanism of acute antibody-mediated rejection leading to graft loss and the mechanisms of accommodation permitting graft survival in ABO-incompatible kidney transplantation. As previously noted, accommodation occurs only with (i) post-transplant suppression of glycosyltransferase, a product of ABO histo-blood group genes in the graft and (ii) prevention of antigen-antibody reactions and delayed hyperacute rejection due to reduced antigenicity of enzyme-regulated histo-blood group antigens. This article discusses the mechanism of ABO histo-blood group glycosyltransferase suppression. Accommodation is always established in successful ABO-incompatible organ grafts and ABO-minor mismatch bone marrow transplantation. In the former, accommodation develops even though ABO histo-blood types of the recipient and the donor are incompatible. In the latter, infusion of donor-derived bone marrow causes the recipient's blood to be eventually replaced by blood of the donor's type. However, the recipient's organs retain their original tissue type. In successful bone marrow engraftment, accommodation is established regardless of ABO-incompatibility. In organ transplantation the recipient's ABO histo-blood type regulates the graft's ABO histo-blood type, while in bone marrow transplantation the new ABO histo-blood type from the donor suppresses and regulates the ABO histo-blood type in recipient organs. In other words, bone marrow-derived histo-blood type regulates the histo-blood type of the organs.

Relationship Between Anti-ABO Antibody Production and Hemolytic Anemia After Minor ABO-Mismatched Living-Donor Lobar Lung Transplantation

With the shortage of lung donors, we have performed 28 living donor lobar lung transplantations (LDLLTs) since October 1998. Although lungs from ABO-identical donors were used if available, lungs were transplanted from donors showing minor ABO mismatches when suitable ABO-identical donors were not found. The aim of this study was to evaluate the relationship between anti-ABO antibody (Ab) production and the outcomes of lung transplantation with ABO-mismatched living donor lungs. We reviewed 28 patients (28 recipients with 55 donors) who underwent LDLLT between October 1998 and March 2004. In this patient population, 13 patients (46.4%) received minor ABO-mismatched transplants. Anti-A or B-IgG or IgM antibodies (Abs) in the serum and red cell elutes were examined. All 28 patients are alive and well at a mean observation period of 28.0 months (ranging from 5 to 70 months). Anti-A or B-IgG or IgM Abs were detected in 5 out of 13 minor ABO-mismatched patients (38.5%) after transplantation, but only one of them showed evidence of severe hemolytic anemia due to donor-derived antibodies. The titer of that patient's Abs was higher than that of the other recipients. Anti-ABO antibody production and anemia were not associated with gender, age, relationship between donors and recipients, and HLA matching. We conclude that LDLLT across ABO mismatches is an acceptable treatment for end-stage lung disease.

ABO Incompatibility Is a Risk Factor for Intestinal Thrombotic Microangiopathy (TMA) after Allogeneic Stem Cell Transplantation.

Intestinal thrombotic microangiopathy (TMA) after allogeneic stem cell transplantation is emerging as a major clinical issue, which is different from aGVHD in pathogenesis and clinical management. We performed a retrospective analysis of 140 pediatric patients with acute leukemia (82 ALL and 58 AML) who underwent allogeneic stem cell transplantation in Japanese Red Cross Nagoya First Hospital from 1991 to 2003 (69 from HLA matched sibling, 13 from HLA mismatched family donors and 58 from unrelated volunteer donors). Blood type was matched in 78 patients and mismatched in 62 patients (25 in minor , 26 in major and 11 in bidirectional). Seventeen patients developed intestinal TMA with a cumulative incidence of 13%. The median time to onset was 28 days (range, 10–104 days). Intestinal TMA was defined histopathologically by colonoscopic biopsies in 7 patients and bloody diarrhea and laboratory findings. Intestinal TMA occured in 28% of ABO minor mismatched transplantation, 32.5% of bidirectional, 14.4% of major mismatched and 5.8% in matched transplantation (p<0.01)(Fig1)p. In multivariate analysis, ABO minor mismatched transplants (HR=5.3, 95%CI 1.4–19.7, p=0.01), HLA mismatched related donors (HR=16.6, 95%CI 1.6–173.3, p=0.02 ) and unrelated donors (HR=16.4, 95%CI 2.0–130.6, p<0.01 ) were significantly associsted with the risk of intestinal TMA. The estimated 5-year overall survival (OS) was 47.1% in intestinal TMA patients compared with 56.7% in patients with no intestinal TMA (p=0.18). Intensified immunosuppressants for the treatment of intestinal TMA (n=5) lead to poor OS (20%). Seven out of 12patients (58%) who had reduced immunosuppressant were still alive with a median follow-up of 24 months (p=0.29). Our findings suggest that ABO mismatched transplantation, especially ABO minor mismatch, is a risk factor for developing intestinal TMA. Successful treatment for intestinal TMA by diminishing immunosuppressive drugs is warranted. [Display omitted] [Display omitted]

RELATIONSHIP BETWEEN ANTI-ABO ANTIBODY PRODUCTION AND HEMOLYTIC ANEMIA AFTER MINOR ABO-MISMATCHED LIVING-DONOR LOBAR LUNG TRANSPLANTATION

O481 Aims: To solve the shortage of lung donors, we have performed twenty eight cases of living-donor lobar lung transplantation since October 1998. Although lungs from ABO-identical donors were used if available, in instances when suitable ABO-identical donors were not found, lungs were transplanted from donors showing minor ABO mismatches. It is known that solid organ transplantation from donors with minor ABO mismatches can be complicated by hemolysis. The aim of this study was to evaluate the relationship between anti-ABO antibody production and outcome of lung transplantation performed with ABO-mismatched living-donor lungs. Methods: We reviewed 28 patients (28 recipients with 55 donors) who underwent living-donor lobar lung transplantation between October 1998 and March 2004. In this patient population, thirteen cases (46.4%) were minor ABO-mismatched transplant. Anti-A or B-IgG antibodies (Abs) in the serum and red cell elutes were examined. Results: All of these 28 patients are alive (mean observation period: 23.1 (ranging from 1 to 65) months). Anti-A or B-IgG Abs could be detected in four out of thirteen minor ABO-mismatched patients (30.8%) after transplant, but only one of them (29 year-old woman, bronchiolitis obliterans) had evidence of severe hemolytic anemia due to donor-derived antibodies. The titer of anti-A-IgG Abs in her serum increased to 1:32 on day 26, and her hemoglobin level decreased from 11.6 g/dL to 6.6 g/dL with signs of hemolysis. She required 2800 mL of group O concentrated RBCs. On the other hand, the titer of Abs in other mismatched patients’ serum reached from 1:4 to 1:16 (mean 1:8), and there was no signs of anemia. Anti-ABO antibody production and anemia were not associated with gender, age, relationship between donors and recipients, and HLA matching. The incidence of acute rejection, chronic rejection, and infection was not affected by ABO mismatch. Conclusions: We report thirteen cases of minor ABO-mismatched living-donor lobar lung transplantation. Four of them developed anti-A or B-IgG antibodies in the serum, but only one of them showed hemolytic anemia. The titer of anti-A-IgG Abs of this patient was higher than Abs of others, but the mechanism of the phenomenon is obscure. We conclude that living-donor lobar lung transplantation across ABO mismatches is an acceptable treatment for end-stage lung diseases.

Significant numbers of apheresis-derived group O platelet units have "high-titer" anti-A/A,B: implications for transfusion policy.

Transfusion of group O single-donor apheresis PLTs (SDP) to group A recipients has resulted in intravascular hemolysis and mortality. Owing to low availability of type-specific SDPs, transfusion services sometimes issue ABO-mismatched PLTs. After observing two cases of acute hemolysis following infusion of O SDPs to group A patients, where both recipient eluates revealed anti-A specificity, a prospective study to determine the prevalence of "high-titer" anti-A/A,B in group O SDPs was commenced. One hundred group O SDP samples were tested. Titers of at least 64 and/or 256 from either buffered (generally reflective of IgM antibodies) or anti-IgG gel cards, respectively, were considered critically high. Twenty-eight and 39 percent of samples revealed critically high anti-A/A,B IgM and IgG titers, respectively. IgM titers were at 1:64 (18%), 128 (6%), and 256 (4%), whereas IgG titers were at 1:256 (28%), 512 (7%), 1024 (2%), and 2048 (2%). The prevalence of critical anti-A/A,B titers in group O SDPs is relatively high. Thus, the risk of minor side ABO mismatch and potential intravascular hemolysis during group O SDP transfusion to group A recipients may be significant. Based on these data, a policy was instituted to test anti-A/A,B titers in O SDPs prior to "out-of-group" transfusion.

Blood versus marrow hematopoietic allogeneic graft

Allogeneic G-CSF-mobilized blood cell transplantation (BCT), an alternative to allogeneic bone marrow transplantation (BMT), is associated with enhanced engraftment and accelerated hematopoietic recovery. In addition, immune reconstitution and overall alloreactivity after BCT versus BMT differ significantly. Indeed, despite an increased number of donor T cells infused, the incidence of acute graft-versus-host disease (GvHD) after BCT appears to remain identical or lesser than after BMT. On the other hand, a higher risk of chronic GvHD has been reported after BCT. In a SFGM phase III trial, 101 patients with early leukemia and an HLA-matched sibling donor randomly received a BCT or BMT. BCT was associated with a higher number of infused CD34+ cells, accelerated platelet and neutrophil reconstitution, fewer platelet transfusions and similar acute GvHD incidence. However, chronic GvHD occurred more frequently after BCT. With a median follow-up of 20 months, relapse, survival and leukemia-free survival were not different. In the course of this study, immune parameters related to the graft as well as to early reconstitution were prospectively examined. T cells subsets, B cells, NK cells and monocytes numbers were significantly higher in BC grafts (versus BM). T cells in BC grafts were less activated than in BM grafts. Frequency of IFN-γ, IL-2- and TNF-α-secreting cells and single-cell IFN-γ production potential was reduced in BC graft. One month after BCT, blood T-cell counts were 3-fold higher than after BMT. Moreover, post-BCT T cells were less activated and counts correlated with the number of T cells infused with the graft, which was not the case after BMT. Several acute hemolysis episodes, resulting from anti-A and/or -B donor-derived Ab directed at Ag present on recipient red blood cells (minor ABO mismatch), have been described after BCT. Recipients indeed exhibited significantly increased anti-A and/or -B Ab titers after BCT, particularly in the setting of a “minor” ABO mismatch. Furthermore, the frequency of anti-HLA Ab early after BCT was significantly increased (despite the reduction in platelet transfusion requirements). The higher number of activated B cells and/or CD4 T cells and monocytes in a BCT graft and/or the higher number of circulating CD4 T- and B-cells after BCT could be associated with the enhanced alloAb production. G-CSF-induced TH2 cytokine profile of the T cells present in the graft could also be contributive. Recent studies have determined that BC grafts contained a higher number of type 2 dendritic cells (DC2), themselves associated with high frequencies of TH2 CD4+ cells. Since chronic GvHD is associated with the occurrence of Ab-mediated auto-immune-like syndromes, it is tempting to speculate that a higher incidence of chronic GvHD may result from these findings. In conclusion, BCT results in clinically relevant distinct hematopoietic and immune reconstitution patterns.

Severe immune hemolysis after minor ABO-mismatched allogeneic peripheral blood progenitor cell transplantation occurs more frequently after nonmyeloablative than myeloablative conditioning.

Hemolysis as a result of donor-recipient minor ABO mismatching is a complication of allogeneic peripheral blood progenitor cell (PBPC) transplantation (PBPCT). The increased B-lymphocyte content of PBPC grafts and immunosuppressive regimens without methotrexate (MTX) may increase incidence and severity of this event. A total of 93 patients were analyzed after allogeneic PBPCT. In 25 (27%) cases, minor (n=21) or bidirectional (n=4) ABO mismatching was present. Of these, 15 patients received myeloablative and 10 received nonmyeloablative conditioning regimens. For GVHD, prophylaxis cyclosporin A (CsA) alone (n=2) or CsA with MTX (n=13) was given after myeloablative conditioning and CsA with mycophenolate mofetil (MMF) after nonmyeloablative conditioning (n=10). Hemolysis occurred in 4 out of 25 (16%) patients with minor or bidirectional ABO mismatching only. Three patients underwent nonmyeloablative conditioning and were given CsA with MMF, and one patient underwent myeloablative conditioning and was given CsA alone for GVHD prophylaxis. Hemolysis began 7 to 10 days after transplantation, and donor type alloantibodies were detectable concomitantly with recipients type RBCs. Patients receiving minor or bidirectional ABO-mismatched PBPC grafts and GVHD prophylaxis without MTX are at risk of hemolysis. Prophylactic interventions in patients before minor ABO-mismatched PBPCT not receiving MTX should be taken into consideration. Careful monitoring of hemolysis parameters during the first 15 days after PBPCT transplantation is mandatory.

Allogeneic peripheral blood stem cell versus bone marrow transplantations: CD34+ cell mobilisation, graft composition, immune reconstitution and clinical outcome

The use of peripheral blood, after G-CSF mobilization, as a source of allogeneic hematopoietic stem cells is being increasingly considered. Some significant data were given by 3 large randomized trials comparing bone marrow (BM) and peripheral blood stem cells (PBSC). Numbers of CD34+ and CD3+ harvested cells were significantly higher in PBSCT group and the hematopoietic recovery was significantly faster after PBSCT. While the American trial showed significant increased rates of acute GVHD and an higher survival and disease-free survival in favour of PBSC, the 2 other studies showed a significant increase of chronic GVHD after PBSCT. The French group investigated whether there was a correlation between cellular composition of PBSC and outcome after transplant. Neither hematological recovery, acute or chronic GVHD nor disease relapse, were significantly associated with CD3+ cell doses. However, high CD34+ cell doses (>8.3×106/Kg) were associated with faster hematopoietic recovery and higher probability of extensive cGVHD at 5 years and DFS was significantly higher in patients receiving low CD34+ cell dose. In parallel, in this study, we evaluated and compared different immune parameters in the graft and after transplantation. Absolute values of mononuclear cells/kg were significantly higher in PBSC grafts than in BM grafts. Analysis of CD25, CD95, HLA-DR and CD45RA expression showed that PBSC grafts T cells exhibited a lower activation level. We found no preferential G-CSF-induced mobilisation of so-called “suppressive” CD3+ cells. In contrast, G-CSF reduced 2- to 3-fold the frequency of IFN-gamma-, IL-2- and TNF-alpha-secreting cells within the NK, NK-T and T-cell subsets and severely reduced the potential for IFN-gamma production at the single-cell level. Thirty days after transplantation, T-cell blood counts were 3-fold higher after PBSC. After PBSCT, T cells were less activated, and at day 30 CD4+, CD8+, CD45RA+ counts were correlated with the number of mononuclear cells infused with the graft, this was not observed after BMT. We showed that Anti-A and/or anti-B Ab titers were significantly increased in PBSCT vs BMT recipients at day 30 and mostly after minor ABO mismatch transplant. PBSCT were significantly associated with increased detection of anti-HLA antibodies early after transplantation. This difference was further increased when analysis was restricted to anti-HLA IgG Ab-negative donor/recipient pairs. The higher number of B cells in the PBSC could be associated with enhanced Ab production early after transplantation. Regarding mini-allotransplants, in France, in a retrospective analysis, we did not show any difference between PBSC and BM in term of disease response, chimerism and overall survival but a significant impact of number of CD34+ cells on early chimerism after transplant. This kind of tranplant might include donor lymphocyte infusion (DLI) strategy and we showed in our center that previous PBSC donation selectively impaired the yields of total MNC and total CD3+ cells recovery after donation but did not affect neither CD19+ nor CD3− CD56+ recoveries when compared to the cohort of BM donations. The use of G-CSF mobilised peripheral blood, as a source of allogeneic stem cells is increasingly considered, especially for mini-allotransplants which justify further studies to identify the different biological characteristics of this source and its clinical impact. *** DIRECT SUPPORT *** A00RC002 00004

Influence of the hematopoietic stem cell source on early immunohematologic reconstitution after allogeneic transplantation

AbstractSeveral acute hemolysis episodes, sometimes lethal, have been recently described after transplantation of allogeneic peripheral blood hematopoietic stem cells (PBHSCs). Hemolysis resulted from the production of donor-derived antibodies (Abs) directed at ABO antigens (Ags) present on recipient red blood cells (RBCs). A multicenter randomized phase III clinical study comparing allogeneic PBHSC transplantation (PBHSCT) versus bone marrow hematopoietic stem cell transplantation (BMHSCT) has been conducted in France. In the course of this study, serum anti-A and/or anti-B Ab titers were compared before the conditioning regimen and on day +30 after transplantation in 49 consecutive evaluable PBHSCT (n = 21) or BMHSCT (n = 28) recipients. PBHSCT resulted in a higher frequency of increased anti-A and/or anti-B Ab titers 30 days after transplantation as compared to BMHSCT: 8 (38%) of 21 versus 3 (11%) of 28 (P = .04). In PBHSCT recipients, increased titers were observed mostly after receiving a minor ABO mismatch transplant: 5 of 7 versus 3 of 14 in the absence of any minor ABO mismatch (P = .05), whereas this was not the case after BMHSCT: 1 of 8 versus 2 of 20. Anti-A and/or anti-B serum Abs detectable at day +30 after PBHSCT were always directed against A and/or B Ags absent both on donor and recipient RBCs. Finally, 3 of 21 PBHSCT versus 0 of 28 BMHSCT recipients developed anti-allogeneic RBC Abs other than ABO (P = .07). Overall, the data strongly suggest that immunohematologic reconstitution differs significantly after granulocyte colony-stimulating factor–mobilized PBHSCT when compared to BMHSCT. Such a difference could contribute to the acute hemolysis described after PBHSCT as well as to distinct alloreactivity after PBHSCT.

Role of the ABO system in transplants and grafts

The structures and locations of the glucidic molecules in the ABO system vary according to the tissues, ontogenesis and individuals. Although their physiological role is not well established, they are considered as very important factors in transplantations. When the ABO identity is not taken into account, hyperacute, acute, and chronic rejections, or hemolysis and tolerance phenomenon may occur but the incidence of these problems varies according to the tissues. In ABO minor mismatch, the transplantation is always possible, but is associated with worse long term graft survival, except for bone marrow. In ABO major mismatch, the frequency of hyperacute rejections remains the main problem, although the frequency is nil for bone marrow, very low for the liver, quite important for the kidney, and high for heart transplantations. Thus, the ABO group barrier is not absolute but must still be taken into account for allogenic transplantations.