Antibody-mediated Vascular Rejection Research Articles

P8.109: Simultaneous Vascular and Antibody-Mediated Rejection (AMR) in Pediatric Patients Caused Poor Prognosis in Renal Allograft

Introduction: The prognostic significance of simultaneous vascular rejection (VR) and AMR on graft survival is not clear enough, especially in the pediatric population. Accordingly, this study aims to determine the impact of simultaneous VR and AMR on the development of transplant glomerulopathy (TG) and interstitial fibrosis (IF) with the resulting graft survival. Methods: Forty-five recipients younger than 18 were separated into Group 1 patients (n:25) with pure AMR and Group 2 patients (n:20) with simultaneous VR+AMR. Tubular expression of TNF-α, TGF-β, and HLA-DR was evaluated. Peritubular capillary (PTC) and interstitial leukocytes were highlighted with TNF-α, HLA-DR, and CD68. The loss of HLA-DR expression on PTCs was studied to determine the PTC destruction. Diffuse IF and TG development were analyzed in the follow-up biopsies. Results: The response of Group 2 patients to rejection therapy was lower than Group 1 (p<0.001). PTC C4d expression was found higher in Group 2 than Group 1 (P<0.001). Group 2 showed a higher PTC destruction, IF, and TG incidence than Group 1(P<0.01). The development of IF and TG increases with the increasing degree of glomerulitis, C4d expression, and PTC destruction (p<0.01). Tubular and interstitial TNF-α, TGF-β, and HLA-DR expressions were found higher in Group 2 compared to Group 1 (p<0.01). The degree of PTC destruction and C4d expression increased with increasing leukocyte and macrophage infiltration in PTCs and interstitium (p<0.001). The development time of IF and TG decreased with increasing intensity of PTC and interstitial infiltration, glomerulitis, PTC destruction, and C4d expression (p<0.01). Also, the development of IF and TG shortened with increasing HLA-DR, TNF-α expression in inflammatory cells and increasing TNF-α, TGF-β, HLA-DR expression in tubular cells (P<0.01). Overall, the 1-, 3- and 5-year graft survival was 96%, 92%, and 79%, respectively, for Group 1 patients, while 95%, 40%, and 10% respectively for Group 2 recipients (p<0.001). Conclusion: The prognosis and course of antibody-mediated vascular rejection are noticeably different from pure AMR, with antibody-mediated vascular rejection having the poorest outcome through leading the early development of IF and TG via augmenting inflammatory and fibrotic pathways. Thus, developing new treatment strategies for antibody-mediated vascular rejection could salvage many kidney allografts.

The Clinical and Pathologic Phenotype of Antibody-Mediated Vascular Rejection Diagnosed Using Arterial C4d Immunoperoxidase

IntroductionThe diagnosis of antibody-mediated vascular rejection (AM-VR) should be reliable and accurate. We hypothesized that arterial C4d (C4dart) immunoperoxidase deposition represents endothelial interaction with antibody.MethodsFrom 3309 consecutive, kidney transplant biopsies from a single center, 100 vascular rejection (VR) cases were compared against rejection without arteritis (n = 540) and normal controls (n = 1108). The clinical utility of C4dart for diagnosis and classification of AM-VR was evaluated against an independent reference test.ResultsC4dart occurred in 20.4% of acute, 11.0% of subclinical, and 46% of VR episodes. Semiquantitative C4dart score significantly correlated with immunodominant donor-specific antibodies (DSAs) (rho = 0.500, P < 0.001), peritubular capillary C4d (C4dptc), microvascular inflammation, and Banff v scores. Banff v3 arteritis suggested AM-VR. Addition of C4dart to Banff antibody-mediated rejection (AMR) schema increased diagnostic sensitivity for AM-VR from 57.9% to 93.0%, accuracy 74.0% to 92.0%, and specificity 95.4% to 90.2% versus Banff 2019 (using C4dptc). Death-censored graft failure was associated with C4dart AM-VR criteria using Cox regression (adjusted hazard ratio [HR] 4.310, 95% CI 1.322–14.052, P = 0.015). VR was then etiologically classified into AM-VR (n = 57, including 36 mixed VR) or “pure” (TCM-VR, n = 43). AM-VR occurred within all post-transplant periods, characterized by greater total, interstitial, and microvascular inflammation, arterial and peritubular C4d, DSA levels, and graft failure rates compared with TCM-VR. Mixed VR kidneys had the greatest inflammatory burden and graft loss (P < 0.001).ConclusionC4dart is a suggestive biomarker of the humoral alloresponse toward muscular arteries. Inclusion of C4dart into the Banff schema improved its diagnostic performance for detection of AM-VR and etiologic classification of arteritis.

The Pathological and Clinical Diversity of Acute Vascular Rejection in Kidney Transplantation.

Vascular rejection (VR) is characterized by arteritis, steroid resistance, and increased graft loss but is poorly described using modern diagnostics. We screened 3715 consecutive biopsies and retrospectively evaluated clinical and histological phenotypes of VR (n = 100) against rejection without arteritis (v0REJ, n = 540) and normal controls (n = 1108). Biopsy sample size affected the likelihood of arterial sampling, VR diagnosis, and final Banff v scores ( P < 0.001). Local v and cv scores were greatest in larger arteries (n = 258). VR comprised 15.6% of all rejection episodes, presented earlier (median 1.0 mo, interquartile range, 0.4-8 mo) with higher serum creatinine levels and inferior graft survival, versus v0REJ ( P < 0.001). Early VR (≤1 mo) was common (54%) and predicted by sensitization, delayed function, and prior corticosteroid use, with associated acute dysfunction and optimal therapeutic response, independent of Banff v score. Late VR followed under-immunosuppression in 71.4% (noncompliance 38.8%, iatrogenic 32.6%), and was associated with chronic interstitial fibrosis, incomplete renal functional recovery and persistent inflammation using sequential histopathology. The etiology was "pure" antibody-mediated VR (n = 21), mixed VR (n = 36), and "pure" T cell-mediated VR (n = 43). Isolated VR (n = 34, Banff i < 1 without tubulitis) comprised 24 T cell-mediated VR and 10 antibody-mediated VR, presenting with mild renal dysfunction, minimal Banff acute scores, and better graft survival compared with inflamed VR. Interstitial inflammation influenced acute renal dysfunction and early treatment response, whereas chronic tubulointerstitial damage determined long-term graft loss. VR is a heterogenous entity influenced by time-of-onset, pathophysiology, accompanying interstitial inflammation and fibrosis. Adequate histological sampling is essential for its accurate diagnostic classification and treatment.

Non-HLA agonistic anti-angiotensin II type 1 receptor antibodies induce a distinctive phenotype of antibody-mediated rejection in kidney transplant recipients

Anti-angiotensin II type 1 receptor (AT1R) antibodies have been associated with allograft rejection. We hypothesized that circulating AT1R antibodies might identify kidney transplant recipients at increased risk of allograft rejection and loss who are not identified by the HLA system. We prospectively enrolled 1845 kidney transplant recipients from two centers. Donor-specific HLA antibodies (DSAs) and AT1R antibodies were measured at the time of the first acute rejection episode or at 1 year post-transplant. Allograft biopsy was performed to evaluate the rejection phenotype and to assess for endothelial activation. Overall, 371 (20.1%) participants had AT1R antibodies, 334 (18.1%) had DSAs, and 133 (7.2%) had both. AT1R antibodies were associated with an increased risk of allograft loss (adjusted HR 1.49, 95% CI 1.07-2.06 for AT1R antibodies alone and 2.26, 95% CI 1.52-3.36 for AT1R antibodies and DSAs). Participants with AT1R antibodies had a higher incidence of antibody-mediated rejection (AMR) compared with participants without AT1R antibodies (25.0% vs. 12.9%). Among 77 participants with histological features of AMR but without DSAs, 51 (66.2%) had AT1R antibodies. Compared to participants with prototypical DSA-mediated rejection, those with AT1R antibody-associated rejection had a higher prevalence of hypertension, more vascular rejection with arterial inflammation, higher levels of endothelial-associated transcripts, and lack of complement deposition in allograft capillaries. Thus, AT1R antibodies may identify kidney transplant recipients at high risk of allograft rejection and loss, independent of the HLA system. Recognition of complement-independent AT1R antibody-mediated vascular rejection could lead to the development of new treatment strategies to improve allograft survival.

Significance of Antibody-Mediated Vascular Rejection (AMVR) on Graft Survival

Introduction Traditionally, endarteritis accepted to associate with cellular rejection. Nevertheless, some of the patients with AMR also had endarteritis at the same time. The risk of graft loss was nine times higher in AMVR than T cell-mediated rejection without endarteritis. However, the importance of the endarteritis on the graft survival in recipients with AMR is controversial. Thus we aimed to understand the prognostic value of the presence of endarteritis in recipients with AMR. Materials and Methods Among 155 recipients 72 (46,5%)had pure AMR (Group 1) while 83 (53,5%) had both AMR and endarteritis (Group 2). Endarteritis graded according to Banff. First indication biopsies of all cases reevaluated and the intensity of interstitial, glomerular and peritubular capillary (PTC) inflammation, neutrophil, macrophage and lymphocyte infiltration graded. HLA-DR expression in the arteries, PTCs, and tubules examined. The loss of DR expression on PTCs accepted as the destruction of PTCs. Follow-up biopsies analyzed for the development of interstitial fibrosis (IF), transplant glomerulopathy (TG) and transplant arteriopathy (TA). Results The extensity of the PTC and arterial C4d expression and the degree of PTC destruction found higher in Group 2 compared to Group 1 (P<.001).The degree of the interstitial eosinophil, plasma, and macrophage infiltration found higher in Group 2 patients than Group 1 (p<.001). Also, the intensity of inflammatory cells and neutrophils in both glomeruli and PTCs found higher in Group 2 compared to Group 1 (p<.001). Compared to Group 1 patients, Group 2 patients showed a higher incidence of IF, TG and TA in follow-up biopsies (p<.01).The development of IF and TG increases with the increasing degree of glomerulitis, PTC-itis, C4d expression and PTC destruction (p<.01). Also, the time of the development of IF and TG decreased with increasing intensity of PTC and interstitial infiltration, glomerulitis, PTC destruction and C4d expression (p<.01). The presence of the eosinophil and macrophage infiltration on the wall of arteries of recipients with AMVR rises the risk of the development of TG and TA (p<.01). Also, patients who had arterial C4d staining had a higher risk of TG, TA and graft loss (p<.001). The response to rejection therapy was lower in Group 2 recipients compared to Group 1 patients (p<.001). Overall the 3- and 5-year graft survival was 98%, and 85% respectively for Group 1 patients while it was 57%, and 27% respectively for Group 2 (p<.001). Conclusion Our results have underlined the importance of the presence of endarteritis in AMR. We showed that the course of AMVR are noticeably different from pure AMR, with AMVR having the worst outcome through leading the early development of IF, TG, and TA via augmenting inflammatory and fibrotic pathways. Thus the development of new treatment strategies for AMVR could salvage many kidney allografts.

Isolated v-lesion represents a benign phenotype of vascular rejection of the kidney allograft - a retrospective study.

While the detrimental impact of the humoral acute vascular rejection (AVR) phenotype is recognized, the prognostic significance of isolated v-lesion (IV) remains unclear. In this retrospective single-centre study, AVR was found in 98 of 1015 patients (9.7%) who had undergone kidney transplantation in 2010-2014, with donor-specific antibodies (DSA) evaluated in all of them. The outcome of four AVR phenotypes was evaluated during median follow-up of 59 months; in 25 patients with IV, 18 with T-cell-mediated vascular rejection (TCMVR), 19 with antibody-mediated vascular rejection (AMVR) and 36 with suspected antibody-mediated rejection (sAMVR). AVR was diagnosed mainly by for-cause biopsy (81%) early after transplantation (median 19 POD) and appeared as mild-grade intimal arteritis. IV occurred in low-sensitized patients after the first transplantation (96%) in the absence of DSA. IV responded satisfactorily to treatment (88%), showed no persistence of rejection in surveillance biopsy, and had stable graft function, minimal proteinuria and excellent DCGS (96%). Contrary to that, Kaplan-Meier estimate of 3-year DCGS of AMVR was 66% (log-rank = 0.0004). Early IV represents a benign phenotype of AVR with a favourable outcome. This study prompts further research to evaluate the nature of IV before considering any change in the classification and management.

Antibody-mediated rejection: New approaches in prevention and management.

Despite the success of desensitization protocols, antibody-mediated rejection (AMR) remains a significant contributor to renal allograft failure in patients with donor-specific antibodies. Plasmapheresis and high-dose intravenous immunoglobulin have proved to be effective treatments to prevent and treat AMR, but irreversible injury in the form of transplant glomerulopathy can commonly manifest months to years later. There is an unmet need to improve the outcomes for patients at risk for AMR. Updated Banff criteria now take into account the increasing understanding of the complex and heterogeneous nature of AMR phenotypes, including the timing of rejection, subclinical and chronic AMR, C4d-negative AMR, and antibody-mediated vascular rejection. Treatment for AMR is not standardized, and there is little in the way of evidence-based treatment guidelines. Refining more precisely the mechanisms of injury responsible for different AMR phenotypes and establishing relevant surrogate endpoints to facilitate more informative studies will likely allow for more accurate determination of prognosis and efficacious intervention using new therapeutic approaches. In addition to plasma exchange and intravenous immunoglobulin, a number of other add-on therapies have been tried in small studies without consistent benefit, including anti-CD20, proteasome inhibitors, complement inhibitors, anti-interleukin-6 receptor blockers, and immunoglobulin G-degrading enzyme of Streptococcus pyogenes (called IdeS).

Comparison of Pediatric Patients with Pure Antibody-mediated Rejection (AMR) and Recipients with both AMR and Vascular Rejection in the Development of Interstitial Fibrosis and Transplant Glomerulopathy

Introduction: The importance of the vascular rejection (VR) on the graft survival in recipients with antibody-mediated rejection (AMR) is controversial. Thus, we aimed to understand first the prognostic value of the presence of VR in children with AMR and second the impact of AMR and VR on the development of interstitial fibrosis (IF) and transplant glomerulopathy (TG). Methods: Among 45 pediatric patients 25 had pure AMR (Group 1) while 20 had both AMR and VR (Group 2). Expressions of tubular TNF-α, TGF-β, and HLA-DR were studied. All infiltrated leukocytes both in the peritubular capillaries (PTCs) and interstitium highlighted with TNF-α, HLA-DR, and CD68. PTC HLA-DR expression examined to determine the extension of the destruction of PTCs. Follow-up biopsies analyzed for the development of diffuse IF and TG. Results: The response to rejection therapy was lower in Group 2 recipients compared to Group 1 patients (p < 0.001). The extensity of PTC C4d expression found higher in Group 2 compared to Group 1 (P < 0.001) and also, the PTC destruction which noted with decreasing expression of PTC-DR expression was found higher in Group 2. Compared to Group 1 patients, Group 2 patients showed a higher incidence of IF and TG in follow-up biopsies (p < 0.01). The development of IF and TG increases with the increasing degree of glomerulitis, C4d expression and PTC destruction (p < 0.01). Compared to Group 1 patients, Group 2 showed higher expression of TNF-α, TGF-β, and HLA-DR both on tubules and infiltrated inflammatory cells (p < 0.01). PTC C4d expression and the degree of PTC destruction increased with increasing degree of leukocyte and macrophage infiltration both in PTCs and interstitium (p < 0.001). The time of the development of IF and TG decreased with increasing intensity of PTC and interstitial infiltration, glomerulitis, PTC destruction and C4d expression (p < 0.01). Also, the development of IF and TG shortened with increasing HLA-DR, TNF-α expression in inflammatory cells and increasing TNF-α, TGF-β, HLA-DR expression in tubular cells (P < 0.01). Overall the 1-, 3- and 5-year graft survival was 96%, 92% and 79% respectively for Group 1 patients while it was 95%, 40%, and 10% respectively for Group 2 recipients (p < 0.001). Conclusion: We pointed out that the prognosis and course of antibody-mediated vascular rejection are noticeably different from pure AMR, with antibody-mediated vascular rejection having the poorest outcome through leading the early development of IF and TG via augmenting inflammatory and fibrotic pathways. Thus, the development of new treatment strategies for antibody-mediated vascular rejection could salvage many kidney allografts.

Antibody-mediated vascular rejection of kidney allograft: characterization of different kidney allograft rejection phenotypes via histology, C4d deposition and donor-specific antibodies

Antibody-mediated vascular rejection of kidney allograft: characterization of different kidney allograft rejection phenotypes via histology, C4d deposition and donor-specific antibodies

Role of Graft-Derived CCL2/MCP-1 in Antibody-Mediated Rejection of Cardiac Allografts.

The role of monocytes/macrophages in antibody-mediated rejection (AMR) remains unclear. We have reported that murine CCR5-/-/CD8-/- recipients produce high titers of donor-specific antibody and reject MHC-mismatched heart allografts. The current studies tested the magnitude of injury and alloimmune responses to grafts deficient in expression of the monocyte chemoattractant MCP-1/CCL2 during AMR. B6.CCR5-/-/CD8-/- recipients rejected MHC-mismatched wild-type A/J allografts with high donor-reactive antibody titers and diffuse C4d deposition in the large vessels and myocardial capillaries, features consistent with AMR. Donor-specific CD4 T cells producing IFN-γ in the recipient spleen were significantly decreased in response to A/J.CCL2-/- vs. A/J allografts and this resulted in decreased donor-reactive antibody production and C4d deposition in allografts in B6. CCR5-/-/CD8-/- recipients at day 7 post-transplant. Consequently, A/J.CCL2-/- allograft survival was slightly but significantly longer than that of A/J allografts (MST: wild-type A/J, day 8 vs. A/J.CCL2-/-, day 10, P < 0.01). Allograft CCL2 deficiency reduced classically activated (M1) macrophage and other inflammatory leukocyte infiltration into the allografts. Strikingly, A/J.CCL2-/- allograft survival was much longer than wild-type A/J allografts in recipients treated with 0.25 mg anti-CD40L mAb at the time of transplant (MST: wild-type A/J, day 21.5 vs. A/J.CCL2-/-, day 58, P < 0.01) with lower titers of donor-reactive antibody and decreased leukocyte infiltration. CCL2 deficiency also reduced pro-fibrotic gene expression and delayed the development of interstitial fibrosis when compared to wild-type A/J allografts. The results indicate that allograft-derived CCL2/MCP-1 plays an important role in directing M1 macrophages and other inflammatory cell infiltration into allografts and in the development of donor-reactive antibody and vascular rejection and suggest CCL2/MCP-1 as a therapeutic target for antibody-mediated vascular rejection and chronic graft injury.

Pathologic basis of antibody-mediated organ transplant rejection

Although antibody-mediated rejection of clinical organ transplants has been recognized more than a half-century ago, our understanding of its pathological/clinical phenotypes has dramatically increased over the past decade. This review highlights the pathological/clinical spectrum of ABMR and discusses its microscopic pathology in relationship with pathogenesis. Newly recognized pathological manifestations of ABMR are: (1) C4d-negative active ABMR, which cannot be definitely diagnosed by current diagnostic systems and often remains underdetected. Novel molecular diagnostic tests can fill this diagnostic gap but these new tests are yet to be prepared for routine application; (2) antibody-mediated vascular rejection, which is misclassified by the current Banff Classification, is therefore inadequately treated and has a high risk for transplant failure; and (3) subclinical (insidious) microvascular inflammation, which can be with or without complement activation, predicts progression to chronic rejection, transplant dysfunction, and failure. A major progress has been made in understanding of ABMR of clinical transplants in the last 5 years. New pathology types of ABMR are not appropriately classified and updates to the Banff diagnostic criteria are required. Better diagnosis would help develop effective antiantibody treatment strategies and improve long-term outcomes for patients.

Antibody-mediated vascular rejection of transplanted kidneys

Antibody-mediated vascular rejection of transplanted kidneys

Antibody-mediated vascular rejection of kidney allografts: a population-based study

Rejection of allografts has always been the major obstacle to transplantation success. We aimed to improve characterisation of different kidney-allograft rejection phenotypes, identify how each one is associated with anti-HLA antibodies, and investigate their distinct prognoses. Patients who underwent ABO-compatible kidney transplantations in Necker Hospital and Saint-Louis Hospital (Paris, France) between Jan 1, 1998, and Dec 31, 2008, were included in our population-based study. We assessed patients who provided biopsy samples for acute allograft rejection, which was defined as the association of deterioration in function and histopathological lesions. The main outcome was kidney allograft loss-ie, return to dialysis. To investigate distinct rejection patterns, we retrospectively assessed rejection episodes with review of graft histology, C4d in allograft biopsies, and donor-specific anti-HLA antibodies. 2079 patients were included in the main analyses, of whom 302 (15%) had acute biopsy-proven rejection. We identified four distinct patterns of kidney allograft rejection: T cell-mediated vascular rejection (26 patients [9%]), antibody-mediated vascular rejection (64 [21%]), T cell-mediated rejection without vasculitis (139 [46%]), and antibody-mediated rejection without vasculitis (73 [24%]). Risk of graft loss was 9·07 times (95 CI 3·62-19·7) higher in antibody-mediated vascular rejection than in T cell-mediated rejection without vasculitis (p<0·0001), compared with an increase of 2·93 times (1·1-7·9; P=0·0237) in antibody-mediated rejection without vasculitis and no significant rise in T cell-mediated vascular rejection (hazard ratio [HR] 1·5, 95% CI 0·33-7·6; p=0·60). We have identified a type of kidney rejection not presently included in classifications: antibody-mediated vascular rejection. Recognition of this distinct phenotype could lead to the development of new treatment strategies that could salvage many kidney allografts. None.

Antibody-mediated vascular rejection: relation to causation

Antibody-mediated vascular rejection: relation to causation

Saphenous Vein Graft Aneurysm After Renal Transplantation: A Case Report

Saphenous Vein Graft Aneurysm After Renal Transplantation: A Case Report

Impact of Repetitive Episodes of Antibody-mediated or Cellular Rejection on Cardiovascular Mortality in Cardiac Transplant Recipients: Defining Rejection Patterns

In our previously published work dealing with antibody-mediated (vascular) rejection (AMR), we defined patterns of rejection (AMR and cellular rejection [CR]) based on a review of biopsy diagnoses taken in the first 6 to 12 weeks post-transplant. We have shown the significance of these pattern designations in relation to patient and allograft outcome in five outcome analyses. The current retrospective analysis was done to determine whether our previous criteria for pattern designations provided the greatest degree of discrimination between AMR and CR. Six hundred sixty-five patients from the U.T.A.H. Cardiac Transplant Program were included in our study. Patients induced with OKT3 immunosuppression were excluded. We analyzed the relationship of a number of either AMR or CR episodes to cardiovascular mortality. We constructed Kaplan-Meier survival curves to assess the impact of incremental numbers of AMR or CR episodes on cardiovascular mortality. Three or more episodes of AMR resulted in a statistically significant increase in cardiovascular mortality. By contrast, CR episodes did not increase the risk of cardiovascular mortality. Based on our findings, we believe that clinical trials should be designed to test treatments based on predominant rejection patterns and that end-points for trials should be defined by number of biopsies positive for either CR or AMR. This approach may lead to improved patient and allograft survival.

T-cell-mediated Rejection of Vascularized Xenografts in the Absence of Induced Anti-donor Antibody Response

T cells are considered to play a major indirect role in the pathogenesis of xenograft vascular rejection, by promoting the induction of anti-donor antibodies that trigger complement- and antibody-dependent cell cytotoxicity. However, how vigorous the T cell xenoresponse is in vivo, and whether, besides their helper function, T cells are capable of directly affecting the graft is still unclear. We have previously shown that cyclosporine A (CsA) withdrawal in accommodated cardiac xenograft recipient allows for a rapid and dense T-cell infiltration, concomitant to an acute graft rejection. In this paper we further characterize the role of T cells in this rejection process and we demonstrate that adoptive transfer of CD4+ T cells in irradiated recipients of long-term cardiac xenografts is sufficient to trigger acute rejection, in the absence of any detectable induced anti-hamster antibody response. Therefore, our data suggest that unusually strong T-cell response will be another major barrier to xenotransplantation, even if antibody-mediated vascular rejection is controlled.

Effect of surrogate tolerogenesis on the vascular rejection of pig heart xenografts.

Organ xenografts are fulminantly rejected by antibody-mediated vascular rejection. Surrogate tolerogenesis (ST), the induction of tolerance within the donor, is effective with aorta xenografts. This preliminary study assesses the effect of ST on preformed antibodies and rejection of porcine heart xenografts. Tolerance to the donor pig was induced by infusing recipient marrow into fetal pigs. Later, pig splenocytes were transfused and heterotopic pig hearts transplanted using chimeric or nonchimeric pigs. Anti-pig antibodies were assessed. With ST alone, xenografts developed cellular rejection at 4-6 days, whereas control grafts developed vascular rejection at 3-4 days (cellular vs. vascular, P<0.03). There was a reduction in preformed antibodies (P<0.03). ST combined with moderate cyclosporine prevented rejection at 9+ and 25 days in sensitized recipients compared with vascular rejection at 0.5-2 days for controls (P<0.07). ST seems to provide protection against vascular rejection. The cellular rejection seems sensitive to cyclosporine.

SPECIFIC INTRAVENOUS CARBOHYDRATE THERAPY A NEW CONCEPT IN INHIBITING ANTIBODY-MEDIATED REJECTION—EXPERIENCE WITH ABO-INCOMPATIBLE CARDIAC ALLOGRAFTING IN THE BABOON

Heterotopic allografting of ABO-incompatible donor hearts in recipient baboons "hyperimmunized" against the incompatible A or B antigen (n = 3) was followed by hyperacute antibody-mediated vascular rejection within a mean of 19 min. The A and B epitopes against which these antibodies are directed are carbohydrates that can be synthesized. The continuous i.v. infusion of the specific synthetic A or B trisaccharide, beginning immediately pre-transplant and continued posttransplant for several days, prolonged allograft survival to a mean of 8 days (n = 2) and prevented antibody-mediated rejection, graft failure resulting from acute cellular rejection. The addition of triple pharmacologic immunosuppressive therapy (n = 4) resulted in prolongation of graft survival to a mean of > 28 days, with one heart still beating at 52 days; all grafts showed features of cellular rejection. "Accommodation" would appear to have developed in several baboons as graft function continued for periods of up to 39 days after discontinuation of carbohydrate therapy. Specific i.v. carbohydrate therapy should allow organ allografting to be performed across the ABO blood group barrier in humans. Furthermore, if the carbohydrate epitopes on the organs of discordant animals (e.g., the pig) against which human xenoreactive antibodies are directed can be confirmed, then this form of therapy might allow successful discordant organ xenotransplantation in man.