Role of antibody in rat renal allograft rejection. II. Failure to enhance renal allografts by sensitization to donor class I antigens presented by donor strain erythrocytes

BN rats were immunized with one or three doses of 1 X 10(8) highly purified LEW erythrocytes (LEW-E) yielding IgM antibody (IgM-BN rats) and IgG antibody (IgG-BN rats) to LEW class I antigens, respectively. LEW kidneys transplanted into IgM-BN rats elicited cytotoxic T cell responses and lymphocytotoxic antibody responses comparable to those elicited by LEW renal grafts in unmodified BN rats. However, LEW kidneys were rejected by IgM-BN hosts in a slightly delayed fashion compared with controls (mean rejection times (MRTs), 9.4 versus 7.1 days); delayed rejection was associated with the absence of anti-LEW IgG hemagglutinins from the recipients' blood and the absence of vasculonecrotic lesions from rejected renal grafts. LEW kidneys inserted into IgG-BN rats were rejected in a slightly accelerated fashion compared with controls (MRT, 6.6 days). Lymphocytotoxins developed in IgG-BN recipients of LEW kidneys in a fashion similar to that of controls, but cytotoxic T cell responses were delayed up to the 6th day after transplantation. These observations confirm our previous finding that cytotoxic T cells do not play a decisive role in acute rejection in this model. The association observed between delayed or accelerated rejection of LEW kidneys by BN rats sensitized with LEW-E and the absence or presence of anti-donor IgG hemagglutinins in the blood of these recipients after transplantation suggests an important role for IgG anti-donor class I antibodies in the rejection of LEW renal allografts by BN rats.     

Estradiol enhances murine cardiac allograft rejection under cyclosporin and can be antagonized by the antiestrogen tamoxifen

BACKGROUND: An increased incidence of acute rejection episodes in female heart transplant recipients has been reported in experimental and clinical studies. However, the exact mechanisms of gender-specific differences in alloreactivity are not completely understood. METHODS: C57BL/10 (H-2b) hearts were transplanted into C3H/He (H-2 k) recipients. Four gender combinations were used to test the influence of donor and recipient sex on graft survival. Recipients were treated with CsA, 17beta-estradiol and/or tamoxifen. Additionally mice were ovariectomized prior to transplantation. RESULTS: Treated with CsA, allograft survival in female recipients was 9.16+/-0.41 days as compared with 15.16+/-1.72 days in males. Estradiol administration and oophorectomy had a significant impact on allograft survival in male and female mice under CsA treatment. Tamoxifen combined with CsA significantly prolonged graft survival in female recipients (13.16+/-1.16 days) as compared with CsA treatment alone (9.16+/-0.41 days). CONCLUSION: Female mice show earlier rejection episodes and a shorter graft survival than males. For the first time, tamoxifen has been shown to have a beneficial effect on heart allograft survival in female recipients.     

预防预致敏受者尸体肾移植术后急性排斥反应的临床研究

目的 探讨HLA配型及新型免疫抑制剂治疗方案对预防致敏患者肾移植术后急性排斥反应的影响.方法 实验组选择46例术前致敏患者(术前PRA>10%),对照组选择同期705例未致敏患者(术前PRA<10%),实验组患者均采用诱导治疗(ATG 100 mg/d,5～7 d)+三联免疫抑制剂维持治疗方案(FK506+MMF+激素),比较两组间患者术后急性排斥反应发病率、移植肾功能延迟恢复比例、移植肾/患者一年存活率,同时分析HLA配型对移植肾急性排斥反应的影响.结果 实验组与对照组急性排斥反应的发病率分别为30.43%和19.57%(P<0.05);移植肾功能延迟恢复发病率分别为60.86%和11.87%(P<0.01).患者一年存活率分别为95.65%和98.44%,一年移植肾存活率分别为93.48%和96.88%;一年时平均血肌肝分别为130 mmol/dL和125 mmol/dL,差异无统计学意义.实验组患者HLA相配率(4.2)明显高于对照组患者(2.8)(P<0.05).实验组中HLA配型2-4错配的患者与0-2错配患者的急性排斥反应发病率有显著性差异,高度致敏患者(移植术前PRA>50%)急性排斥反应发病率较低度致敏患者(PRA 10%～20%)发病率高,移植术后PRA水平持续升高者更容易出现急性排斥反应.结论供、受者之间良好的HLA配型及采用新型免疫抑制药物治疗方案,对预防及减轻致敏患者移植术后急性排斥反应疗效确切.     

Humoral immune responses during acute rejection in rat lung transplantation

The detailed responses of humoral immunity during acute rejection remain obscure in lung transplantation (LTx). In order to clarify the reactions of alloantibodies (allo-Abs) during acute rejection, we demonstrated the time-course of changes in anti-donor Ab reaction in the peripheral blood and deposition in the grafts using a rat LTx model. Lewis (LEW) rats served as recipients for Brown Norway (BN) lung allografts (MHC fully incompatible combination). The left lung was transplanted orthotopically using a cuff technique. Syngeneic transplants (LEW to LEW) served as control. No immunosuppression therapy was administered in this model. We evaluated the alloreactivity against donor in rat recipients by detecting allo-Abs with a flow cytometric cross-match (FCXM) technique. Recipient serum samples were incubated with donor lymphocytes and stained with anti-rat immunoglobulin (Ig), to determine the titers of circulating allo-Abs in the peripheral blood with a three-color FCXM technique. We also examined the deposition of anti-donor Abs (IgG and IgM) in the grafts with an immunofluorescent method. All allografts were completely rejected and lost their aeration within 6 days after LTx. Strong allo-Abs responses of both IgG and IgM were observed in the peripheral blood during acute rejection. The level of IgM allo-Abs had already significantly increased on day 2 at the time of mild rejection; however, IgG Abs did not elevate until day 6, when the grade of rejection was severe. Circulating IgM levels started decreasing on day 8, whereas IgG Abs continued elevating. On the other hand, no evident deposition of allo-Abs in the grafts was observed until day 6. We have shown in this study that circulating IgM allo-Abs was detected at the time of mild allograft rejection, interestingly, before evident deposition in the graft. It might be suggested that allograft rejection progressed without antibody deposition until severe rejection.     

Induction of graft-versus-host disease and rejection by sensitized small bowel allografts

This study was undertaken to investigate under which circumstances graft versus host disease occurs following fully allogenic small bowel transplantation in the rat. To facilitate the development of GVHD, Brown-Norway donors were specifically sensitized against the Lewis hosts prior to transplantation. Additionally, the Lewis recipients were immunocompromised before transplantation using splenectomy, cyclosporine, and antilymphocyte serum. No further immunosuppressive therapy was administered after transplantation. When all pretreatment regimens were used, acute lethal GVHD arose in two of nine animals (22%), whereas in two animals (22%) signs of acute GVHD and rejection were observed concurrently. When recipients of sensitized grafts were pretreated with CsA alone, one of eight animals (12.5%) showed signs of GVHD and rejection. All other animals died of acute rejection without clinical signs of acute GVHD. However, histological signs of GVHD were observed frequently in hosts grafted with a sensitized small bowel transplant. These data show that acute lethal GVHD can occur when an immunocompromised host is grafted with a sensitized intestinal transplant.     

A rat model of chronic allograft liver rejection

INTRODUCTION: The aim of this study was to develop a rat model of chronic irreversible rejection, which is a major causes of late graft loss and retransplantation after orthotopic liver allotransplantation. METHODS: Allogeneic liver transplantation was performed in a rat combination of Dark Agouti (DA) to Brown Norway (BN). Group A was left without treatment, group B received cyclosporine' (CsA; 1 mg/kg/d) and group C, CsA (4 mg/kg/d). Animals were followed for 6 months. Liver tissue was harvested to construct a time course of histological changes after liver transplantation using histopathological and morphometric techniques. We compared the total histological score of rejection activity index and survival rates. RESULTS: In untreated animals, irreversible acute rejection developed, all animals died within 15 days. In the low-dose CsA group, all animals that survived more than 30 days developed moderate to severe manifestations of chronic liver rejection, with graft infiltration, ductular damage or proliferation, obliterative arteriopathy, and liver fibrosis. No apparent histological alterations were observed in group C. Survival analysis showed significant differences between the three groups. CONCLUSIONS: In the rat strain combination of DA --> BN with low-dose immunosuppression, early mild inflammation was followed by the development of chronic rejection.     

Sensitization interval and administration method alter the effect of 15-deoxyspergualin on heart transplantation in sensitized recipient rats

We evaluated the effect of 15-deoxyspergualin (DSG) on accelerated rejection. Brown Norway rats (BN) served as organ donors and Lewis rats (LEW) as recipients. In an accelerated rejection model, after a LEW rat was sensitized with BN skin, a BN heart was transplanted. Various intervals between sensitization and heart transplantation were examined. The heart allografts in sensitized recipients were rejected earlier than those in unmodified recipients regardless of the sensitization interval. DSG (2.5 mg/kg per day), given to the recipients during the sensitization phase, significantly prolonged graft survival compared with the untreated hosts when the sensitization interval was short. When the recipients were treated with DSG after heart transplantation, heart graft survival was significantly prolonged regardless of the sensitization interval. Flow cytometric analysis and complement-dependent cytotoxicity tests revealed that DSG suppressed antidonor antibody formation and that postoperative administration of DSG significantly decreased the proliferation of B cells when the sensitization interval was short and the proliferation of class II antigen-positive cells when the sensitization interval was long.     

Comparison of allogeneic and xenogeneic in vitro T-cell proliferative responses in sensitized patients awaiting kidney transplantation

Highly sensitized patients awaiting kidney transplantation may be potential candidates for future clinical trials using pig organ donors. Because of crossreactivity between human leucocyte antigens (HLA) and swine leucocyte antigens (SLA), such patients might have heightened T-cell responses to porcine xenoantigens. We determined whether lymphocytes from allo-sensitized patients displayed secondary (cyclosporine resistant) T-cell proliferative responses against porcine xenoantigens. Lymphocytes from six non-sensitized, seven sensitized [immunoglobulin G (IgG) panel reactive antibodies (PRA) 11 to 84%], 14 highly sensitized patients (IgG PRA > 84%) and 12 healthy individuals were tested [in the presence and absence of Cyclosporin A (CsA)] to determine their proliferative response to human (allogeneic) and to porcine (xenogeneic) stimulator cells. Lymphocytes from all study groups showed a strong proliferative response to allogeneic and xenogeneic stimulator cells with no significant difference between non-sensitized and sensitized individuals. Addition of CsA (100 and 500 ng/ml) inhibited (>90%) proliferation of lymphocytes from all non-sensitized patients to both allogeneic and xenogeneic stimulators. CsA was less effective at inhibiting proliferation of lymphocytes from sensitized patients and highly sensitized patients to allogeneic stimulators [29% (n=21) and 50% (n=42) respectively were resistant to CsA inhibition (100 ng/ml)]. In contrast, cyclosporine inhibited proliferation of lymphocytes from the majority of sensitized and highly sensitized patients to xenogeneic stimulator cells [14% (n=21) and 14% (n=42) respectively were resistant to CsA inhibition (100 ng/ml)]. HLA sensitized patients awaiting renal transplantation display cyclosporine resistant proliferative T-cell responses to allogeneic stimulators but proliferative responses to xenogeneic stimulators are more amenable to suppression by CsA. This finding suggests that humoral sensitisation to HLA antigens is not necessarily indicative of a heightened in vitro T-cell response to SLA antigens.     

High avidity antibodies to fetal pig pancreas endocrine cells transfer rejection but are not normally generated to fetal pig pancreas xenografts

Previous studies on the contribution of T cell-dependent antibody (Ab) to non-vascular xenograft rejection have yielded conflicting results, being confounded by the presence of recipient T cells and the use of different tissues and immunizing regimens to generate Ab. In the present study, the effect of adoptive transfer of Ab on fetal pig pancreas (FPP) and pig PK15 cell xenografts was examined in T cell-deficient severe combined immune deficiency (SCID) mice. T cell-dependent Abs raised by hyperimmunization with different cell types and by FPP transplantation were compared. Ab raised by hyperimmunization with pig thymocytes exhibited strong binding to pig thymocytes and PK15 cells but did not transfer FPP rejection. IgG1 and IgM, but not IgG3, Abs bound strongly to FPP exocrine and connective tissue, whereas binding to endocrine cells in vitro and in vivo was weak or absent. This pattern of Ab binding was similar to that observed after transplanting FPP into BALB/c mice. Furthermore, serum recovered from BALB/c mice 20 days after FPP transplantation bound strongly to non-endocrine but not endocrine cells and did not transfer FPP rejection. In contrast, serum from mice hyperimmunized with PK15 cells bound strongly to PK15 cells and transferred rejection of intraperitoneal PK15 cells. Furthermore, this serum contained IgG1 and IgM Abs that bound strongly, and IgG3 Abs that bound weakly, to endocrine cells in FPP, and also transferred rejection of FPP in SCID mice. These results indicate that endocrine cells express low concentrations of xenoreactive Ab epitopes and that high Ab concentrations and/or high avidity Abs are required for sufficient endocrine cell binding to cause damage and rejection in the immunodeficient mouse model. Such Abs are not elicited by transplanting FPP into immunocompetent mice. Nevertheless, a contribution of Ab to rejection in immunocompetent mice cannot be excluded.     

大鼠喉移植应用环孢素A的组织学观察

目的研究环孢素Ａ（ＣｓＡ）对同种异体喉移植物排斥反应的抑制功效、相应的组织学改变以及与ＣｓＡ应用剂量之间的关系。方法供体为封闭群ＳＤ大鼠,受体为Ｗｉｓｔａｒ大鼠,将受体分为对照组和两个实验组,实验Ⅰ组和Ⅱ组每天分别经腹腔注射ＣｓＡ１５ｍｇ·ｋｇ－１·ｄ－１和２５ｍｇ·ｋｇ－１·ｄ－１,连续２周。通过受体局部解剖所见和组织学检查来判定同种异体移植物是否存活。结果对照组移植物均出现了明显的急性排斥反应。两实验组术后７天组织学变化较对照组明显为轻,１４天时喉移植物的组织结构保持完整。实验Ⅱ组１４天时有２只动物组织检查显示粘膜及粘膜下层充血水肿和以多形核白细胞为主的炎性细胞浸润,粘膜上皮坏死脱落,溃疡形成和腺体坏死消失等感染征象,另１只则仅表现为轻度的排斥反应。结论ＣｓＡ能有效阻止受体急性排斥反应的发生,其功效与给药途径和剂量关系密切,大剂量ＣｓＡ的应用可能会增加受体的感染机会。     

外用环孢素A联合CTLA4Ig延长异体移植鼠耳存活的研究

目的　探讨局部外用环孢素 A(Cs A)联合细胞毒性淋巴细胞相关抗原 4融合蛋白 (CTL A4 Ig)对异体复合组织移植的免疫抑制及诱导免疫耐受的作用。方法　建立吻合血管的同种异体大鼠耳廓移植模型 ,术后在移植耳皮肤表面外涂 Cs A并联合 CTL A4 Ig腹腔注射治疗 ,观察移植物的排斥反应及存活时间 ,检测移植后受体血清白细胞介素 - 2 (IL- 2 )含量变化。结果　对照组平均存活时间为 (7.8± 1.7)天 ;单纯用 Cs A治疗组为 (15 .2± 1.9)天 ,单纯CTL A4 Ig治疗组为 (16 .6± 2 .1)天 ;Cs A +CTL A4 Ig联合治疗组为 (2 8.8± 3.5 )天 ,与其它各组相比均有统计学意义 (P<0 .0 1) ;且联合治疗组的受体血清 IL - 2含量最低 ,尤以第 5、7天为著 ,与其它各组相比有统计学意义 (P<0 .0 1)。结论　局部外用 Cs A联合 CTL A4 Ig能有效抑制异体复合组织移植排斥反应 ,显著延长移植物存活时间。     

Role of antinuclear antibodies in experimental and clinical liver transplantation

OBJECTIVE: We recently reported that autoreactive antibodies (Abs) against nuclear histone H1 was transiently induced at an early phase after orthotopic liver transplantation (OLT) in a tolerogenic rat OLT model and possessed immunosuppressive activity. It was also reported that nuclear antigen, high-mobility group box 1 (HMGB1) protein was one of the initiators of the immune reaction. The present study sought to evaluate the role of antinuclear Abs in experimental and clinical liver transplantation. MATERIALS AND METHODS: We prepared 3 animal models: natural tolerance model (DA liver into PVG); acute rejection model (DA liver into LEW); and drug-induced tolerance model (acute rejection model + cyclosporine [CsA]). In addition, we examined clinical samples, including 1 drug-free patient, to measure the antihistone H1/HMGB1 titers at various times after OLT. RESULTS: In a natural tolerance model, antihistone H1 and HMGB1 Ab was induced during the rejection and the tolerance induction phases, respectively. Those Ab responses were also confirmed in a drug-induced tolerance model, whereas no such responses were shown in an acute rejection model. In our clinical drug-free patient, antihistone H1/HMGB1 titer was significantly higher after cessation of CsA than that in healthy volunteers. CONCLUSIONS: Antinuclear Ab is actively expressed in accordance with overcoming rejection episodes with subsequent tolerance induction in both a natural tolerance model and a drug-induced tolerance model. We also observed a similar tendency in our clinical drug-free patient. These results suggested that antinuclear Abs may be useful markers to determine the timing to withdraw immunosuppressants.     

Extensive prolongation of rat renal allograft survival following donor or nonspecific transfusions and concomitant immunosuppressant

We report here a marked beneficial effect upon rat renal allograft survival transplanted across a strong histocompatibility barrier (BN----LEW) by pretransplant concomitant donor-strain blood transfusion (DST) and CsA treatment. Comparisons between recipient groups treated with pretransplant nonspecific blood (NST) and concomitant cyclosporine (CsA) or azathioprine (Aza) administration were also made. LEW recipients receiving only a BN renal allograft survived for a geometric average time of 8.9 days. Recipients receiving 1 ml of donor blood at weekly intervals, each week for three weeks prior to transplantation, demonstrated a geometric mean survival time (GMST) of 40.5 days. Recipients receiving this same regimen and concurrent CsA cover (5 mg/kg/day) starting 7 days prior to the first transfusion with discontinuation 5 days prior to transplantation showed extensive prolongation (greater than 100 days). Recipients treated with only CsA cover survived for a GMST of 34.4 days. LEW recipients receiving 1 ml of nonspecific blood at weekly intervals (DA, BUF, WKY, respectively) each week for 3 weeks prior to transplantation were prolonged to 27.7 days. Recipients treated with this same regimen while under CsA cover also demonstrated extended prolongation (greater than 100 days). Recipients receiving multiple donor blood transfusions under Aza (2 mg/kg/day) cover demonstrated lesser prolongation (22.8 days). Recipients receiving the multiple nonspecific blood protocol under Aza cover showed similar prolongation (38.6 days). Recipients treated only with Aza did not show prolonged survival (9.3 days). These differences in survival were considered significant among the 9 transplant groups as determined by ANOVA (P less than 0.001). The majority of recipient groups showed relatively poor renal function over their life spans, independent of whether prolongation occurred. Yet, renal function in the NST or particularly the DST groups covered by pretransplant CsA, demonstrated the best renal function in our laboratory over many years of investigations using the BN----LEW combination. In conclusion, there was a dramatic synergistic beneficial effect of prior multiple DST or NST specific to CsA, as opposed to another immunopharmacologic agent, Aza.     

The selective use of antilymphocyte serum for cyclosporine treated patients with renal allograft dysfunction.

Eighty-seven adult renal allograft recipients were initially treated with cyclosporine-prednisone immunosuppression. Thirty patients experienced no episode of rejection. Antilymphocyte antibody therapy (ALS) was administered to 21 of the 68 recipients of cadaveric donor allografts for either primary allograft dysfunction or acute rejection, and to 6 of 19 recipients of haploidentical, living-related allografts because of steroid-resistant rejection. The cumulative allograft and patient survival for the entire series (follow-up 9-36 months) was 84% and 95%, respectively. This improvement in the rate of successful transplantation can be attributed to the selective addition of ALS therapy to recipients with specific instances of renal allograft dysfunction. In this report, the indications for the use of ALS preparations following prophylactic CsA immunosuppression are reviewed. Experience with the protocols of the ALS administration is also discussed. In selected cases, the administration of either ATG or OKT3 can significantly benefit CsA recipients who experience either primary allograft nonfunction or an epidose of acute rejection.     

Peritransplant treatment with cobalt protoporphyrin attenuates chronic renal allograft rejection

Allogen-independent injury contributes to chronic rejection in renal allografts and heme oxygenase-1 (HO-1) has been shown to be protective in a number of settings. This study evaluated the effect of renal allograft recipient HO-1 up-regulation on chronic rejection in a rat model. Rat (F344 to Lewis) renal transplantation recipients were grouped: (i) cyclosporine (CsA) alone (0.75 mg/kg s.c. x 10 day; n = 5); (ii) CsA + low dose cobalt protoporphyrin (CoPP) an HO-1 inducer (0.5 mg/kg i.p. on days -5,0,5; n = 13) and (iii) CsA + high dose CoPP (5.0 mg/kg i.p. on days -5,0,5; n = 8). Renal function was assessed by serum creatinine levels on day 140. Histopathologic changes in allografts were graded. Morphometric analyses performed to objectively quantify the vascular changes and glomerulosclerosis. HO-1 expression quantified by Western blot and both HO-1 and endothelin (ET-1) localized using immunohistochemistry. Recipients treated with CsA + high dose CoPP had significantly decreased cortical scarring, vascular hyalinization and intimal thickness. They also had a significant, dose-dependent, reduction in luminal obliteration and glomerulosclerosis by morphometric analyses. This freedom from chronic rejection in recipients treated with CoPP translated into quiescent grafts at postoperative day 140 with immunostaining and Western blot demonstrating decreased level of HO-1 versus controls (P = 0.012). In summary, the peritransplant up-regulation of HO-1 in renal allograft recipients significantly attenuates chronic rejection in rat renal allografts by inhibiting transplant vasculopathy.     

Efficacy and safety of tacrolimus versus cyclosporine microemulsion in primary cardiac transplant recipients: 6-month results in Taiwan

INTRODUCTION: This study compared the efficacy and safety of a tacrolimus (TAC)-based with a cyclosporine (CsA)microemulsion-based immunosuppressive regimen in primary cardiac transplantation. METHODS: Heart recipients were randomly assigned to receive either TAC or CsA regimen after sequential induction with rabbit anti-thymoglobulin. Endomyocardial biopsies were performed at weeks 1, 2, 3, and 4 and months 2, 3, and 6. RESULTS: Among 21 adult patients (TAC, 11; CsA, 10) in this study, patient survival rates were 100% in both groups at the end of 6 months. One patient (9%) in the TAC group experienced acute rejection (ISHLT > or = 1B) versus 6 patients (60%) in the CsA group (P = .02). The effects on hematology, biochemistry, cytomegalovirus infection, and hemodynamics were similar in both groups except for better lipid profiles in the TAC group. There were no significant differences in severe adverse events. CONCLUSION: The TAC-based regimen had a lower risk of acute rejection compared with CsA in heart transplant recipients. The safety profiles were similar in both groups. Therefore, TAC is an alternative to CsA as a primary maintenance immunosuppressant in heart transplantation.     

Prolonged cardiac allograft survival in presensitized rats after a high activity Yunnan-cobra venom factor therapy

Complement-dependent antibody-mediated acute humoral rejection is the major obstacle of clinical transplantation across ABO incompatibility and human leukocyte antigen presensitization. We previously demonstrated that Yunnan-cobra venom factor (Y-CVF) could almost completely abrogate complement activity and successfully prevent hyperacute rejection in some xenotransplant models without any obvious toxicity. In this study we investigated whether depletion of complement by Y-CVF prevented acute humoral allograft rejection in presensitized rats thereby prolonging graft survival. METHODS: Presensitization was achieved in Lewis rats by sequential grafting of three full-thickness skin pieces from Brown Norway rats. Serum cytotoxic alloantibody titers were determined by a modified in vitro complement-dependent microcytotoxicity assay. After presensitization, each Lewis rat received a heterotopic Brown Norway cardiac allograft. Fifteen recipients were divided into two groups: (1) no treatment control (n = 7); (2) Y-CVF therapy group (86 u/kg, IV, day -1) (n = 8). After cessation of the heart beat, allograft rejection was confirmed by pathologic as well as IgG and C3 immunohistochemical examinations. RESULTS: The mean graft survival time was significantly prolonged to 99.50 +/- 38.72 hours among rats that received Y-CVF vs 12.71 +/- 13.94 hours in nontreated controls (P < .001). Upon pathological and immunohistochemical examination, acute humoral rejection was mainly exhibited in the control group, whereas acute cellular rejection was mainly displayed in the Y-CVF therapy group. CONCLUSIONS: Our study demonstrated that complement depletion by Y-CVF significantly inhibited acute humoral allograft rejection in presensitized rats. As a therapeutic immunointervention tool for complement, Y-CVF has shown potential efficacy across ABO incompatible and positive cross-match barriers.     

Host presensitization and renal allograft success at a single institution: First transplants.

From June, 1970, to January, 1975, 399 first transplants were performed at the University of Minnesota. Of these 399, 52 had performed antibodies against HLA antigens. When the results of transplantation to these recipients were compared with the results of transplantation to a recipient group matched for age, sex, presence of diabetes, time of transplant, and donor type, no differences were observed. Similarly, no differences were observed when either group of transplant recipients were compared with all first transplant recipients during this period of time. When the results were controlled for diabetes, related or cadaver donation, or degree of presensitization, no differences were observed. Four patients developed hyperacute rejection during this period of time. All four were found to have antibodies to the donor on retrospective analysis utilizing the most sensitive antiglobulin technique. In addition, 65 donor:recipient pairs negative by standard National Institutes of Health and cross-matching techniques proved to have positive prospective cross-matches utilizing the new antiglobulin technique. The correlation between the presence of anti-HL-A antibodies and negative antidonor cross-match and early kidney loss cannot be confirmed at a single institution. The results suggest that a highly sensitive antiglobulin cross-matching technique utilizing sera drawn just prior to the scheduled transplant and cross-matching utilizing the sera bearing the greatest number of anti-HL-A antibodies will eliminate correlation between anti-HL-A antibodies and early graft rejection in the presence of a negative cross-match.     

Elimination of acute GVHD and prolongation of rat pancreas allograft survival with DST cyclosporine, and spleen transplantation

Allogeneic spleen transplantation has been shown to have a tolerizing effect on pancreas allograft survival in rats. In this study we examined the effect of blood transfusions and cyclosporine administration on both rat pancreas allograft survival and acute graft-versus-host disease in BN recipients of Lewis pancreas-spleen allografts. We found that in this strain combination significant pancreas allograft prolongation occurred when the spleen was included en bloc with the pancreas graft. However, 50% of these recipients developed GVHD and died. A single donor-specific transfusion delivered to BN recipients of Lewis pancreas and pancreas-spleen allografts did not extend graft survival, but precluded the development of GVHD. A short, 6-day, and long, 26-day, course of CsA to recipients of pancreas and pancreas-spleen allografts extended graft and animal survival times, although not indefinitely. All pancreas-spleen recipients of both CsA protocols died following acute GVHD. Combined DST and CsA (short and long-course) administration in pancreas-only allograft recipients was deleterious to graft survival, compared with CsA administration alone. However, in pancreas-spleen recipients, combined DST and CsA had an additive effect. Moreover, in DST and long-course CsA-treated pancreas-spleen recipients, indefinite graft survival occurred with no signs of acute GVHD. The beneficial effect of the spleen allograft on pancreas graft survival was not dependent upon GVHD, since splenic-induced prolongation of pancreas graft survival was observed in the F1-donor to parent-recipient combination.     

Effect of prophylaxis with low-dose anti-thymocyte globulin on prevention of acute kidney allograft rejection

INTRODUCTION: During kidney transplantation, the first contact between the recipient's immune system and the donor organ takes place immediately following the arterial anastomosis. The aim of this study was to evaluate the efficacy of a single, low-dose anti-thymocyte globulin (ATG) prophylaxis in the reduction of early acute rejection in renal allograft recipients. METHODS: In a randomized, controlled clinical trial, we studied the rate of acute rejection within the first month of kidney transplantation in patients who had received their transplant at a single center between the years 2004 and 2007. The patients were divided into 2 groups: group 1 (n = 37) received cyclosporine, mycophenolate mofetil or azathioprine, and prednisolone; group 2 (n = 31) received the above-mentioned agents plus a single ATG bolus (Thymoglobulin; SangStat, Lyon, France; 4-5 mg/kg) the night before the transplantation ( approximately 12 hours before the operation). Blood urea and serum creatinine levels were measured regularly in the posttransplantation period. Acute allograft rejection was justified clinically and/or pathologically. Statistical analysis was performed by SPSS 13.0 using Student t test and Fisher exact test. A P value < or = .05 was considered to indicate statistical significance. RESULTS: There were no significant differences regarding the age and gender ratio between the 2 groups. Acute allograft rejection was found in 32.4% (n = 12) of group 1 patients, and was reduced to 12.9% (n = 4) in group 2 (P = .05). Hence, the first-month acute rejection episodes decreased by approximately 60% with ATG prophylaxis in renal transplant recipients. CONCLUSION: Prophylactic administration of a single and low-dose ATG the night before kidney transplantation could reduce the risk of acute allograft rejection in renal transplant recipients. However, further studies with a greater number of patients should be conducted to confirm these results.