吲哚胺2,3-双加氧酶在间充质干细胞诱导肾移植免疫耐受中的作用

目的研究探讨骨髓间充质干细胞(MSC)是否能够诱导肾脏移植物免疫耐受的产生以及吲哚胺2,3-双加氧酶(IDO)在MSC介导免疫调节反应中的作用。方法在BALB/c小鼠接受C57BL/6小鼠移植肾脏后24小时,C57BL/6小鼠来源的正常(wt)或IDO基因敲除(IDO-/-)的MSC(1×106)经静脉注入到移植受体中,分别作为wt-MSC治疗组和IDO-/--MSC治疗组,每组6只。以6只未注射的BALB/c移植小鼠受体为未治疗组。以移植物排斥反应所致小鼠死亡或术后100天设定为研究终点。长期存活的BALB/c肾移植受体在移植术后100天,接受来自C57BL/6供体或第三方移植物供体C3H(H-2k)小鼠的皮肤移植,监测移植皮肤情况。对3组小鼠进行移植物组织病理学观察,免疫组化评估肾脏组织Foxp3+细胞水平。用流式细胞技术进行抗原特异性抗体和细胞表型检测,用混合淋巴细胞反应(MLR)评估树突细胞(DC)和T细胞功能。结果本研究发现wt-MSC治疗可诱导受体产生同种异体移植物免疫耐受,表现为移植物病理检查结果正常、未发现抗原特异性抗体水平升高、免疫耐受受体中耐受性树突细胞(Tol-DC)数量显著增多等。同时,在免疫耐受的受体脾脏和肾移植物中均可发现大量CD4+CD25+Foxp3+调节性T细胞(Treg)。这些结果均提示Treg在MSC诱导免疫耐受中的重要作用。值得关注的是,经IDO-/--MSC处理的移植受体中,MSC丧失了其诱导同种异体移植物的免疫耐受的能力,肾移植物很快被排斥,同时机体移植物的排斥反应变化与未治疗组相同。结论由MSC分泌的IDO通过促进Treg的生成,在诱导肾脏移植免疫耐受中起着关键性的作用。本研究将为MSC在器官移植中的临床应用提供理论及临床转化依据。     

IDO的免疫调节机制及在移植耐受和肿瘤逃逸中的作用

吲哚胺2,3双加氧酶(IDO)是一种能分解色氨酸的细胞内血红素单体蛋白,实验证明通过色氨酸的剥夺和分解产物聚集可以抑制T细胞成熟并促其凋亡.随着对IDO免疫调节机制研究的不断累积,其在器官移植和肿瘤治疗等领域的临床应用前景令人期待.本文就IDO的免疫调节机制及在移植耐受和肿瘤逃逸中的作用做一综述.     

IDO的免疫调节机制及在移植耐受和肿瘤逃逸中的作用

吲哚胺2,3双加氧酶(IDO)是一种能分解色氨酸的细胞内血红素单体蛋白,实验证明通过色氨酸的剥夺和分解产物聚集可以抑制T细胞成熟并促其凋亡.随着对IDO免疫调节机制研究的不断累积,其在器官移植和肿瘤治疗等领域的临床应用前景令人期待.本文就IDO的免疫调节机制及在移植耐受和肿瘤逃逸中的作用做一综述.     

吲哚胺2,3-双加氧酶与胃癌免疫逃逸关系的研究进展

目的探讨吲哚胺2,3双加氧酶(IDO)与胃癌免疫逃逸关系的研究现状及发展趋势。方法回顾性分析近10年来国内、外有关IDO、胃癌免疫逃逸以及二者之间的关系的相关文献。结果胃癌通过CD4+CD8+等调节性T细胞诱导树突状细胞IDO的表达,使得其所处的微环境出现"色氨酸饥饿",从而抑制T细胞增殖;同时,色氨酸代谢产物对T细胞亦存在细胞毒性作用,抑制T细胞的增殖。IDO特异性抑制剂1-MT与化疗药物结合起来在胃癌的治疗上有协同作用。结论 IDO作为免疫调节酶可能在胃癌诱导机体产生免疫耐受过程中起着关键性作用,其可能成为抑制胃恶性肿瘤形成和提高肿瘤免疫治疗效果的新靶点。     

吲哚胺2,3双加氧酶在移植中的作用

吲哚胺2,3双加氧酶(IDO)是一种免疫调节酶,可催化色氨酸分子中吲哚环发生氧化裂解,是其沿犬尿氨酸途径分解代谢的限速酶.IDO具有免疫调节作用,树突状细胞(DC)是一种功能强大的抗原递呈细胞(APC),是唯一能够激活初始型T细胞的APC.IFN-γ等可刺激其表面表达IDO,并通过降解色氨酸,使局部组织中的色氨酸耗竭,代谢产物犬尿氨酸含量增加,从而抑制T细胞的增殖.因此DC表面表达IDO可能在移植中诱导免疫耐受方面起着重要的作用.     

新生猪Sertoli细胞与大鼠胰岛细胞联合移植延长大鼠移植胰岛的存活时间

目的 探讨新生猪Sertoli细胞(NPSCs)与大鼠胰岛细胞联合移植对延长大鼠同种异体胰岛移植物存活时间的作用及其主要的机制.方法 将糖尿病Wistar大鼠随机分为3组.(1)单纯移植组(n=6):单纯移植1500个胰岛当量(IEQ)的SD大鼠胰岛细胞至糖尿病大鼠的左肾包膜下;(2)分侧移植组(n=4):将1500个IEQ的SD大鼠胰岛细胞移植到糖尿病大鼠的左肾包膜下,同时将1×10~7个NPSCs移植到糖尿病大鼠的右肾包膜下;(3)混合移植组(n=6):将1500个IEQ的SD大鼠胰岛细胞和1×10~7个NPSCs混合移植到糖尿病大鼠的左肾包膜下.移植后每天监测各组的血糖水平,以了解移植物的存活时间;移植后发生排斥反应时获取移植物标本,行HE和免疫组织化学染色,观察移植物中CD3~+T淋巴细胞浸润情况及细胞凋亡调控基因(Bcl-2)和血红素氧合酶1(HO-1)基因的表达水平.结果 单纯移植组、分侧移植组和混合移植组胰岛移植物存活时间分别为(5.7±1.0)d、(5.3±0.5)d和(16.3±1.4)d,混合移植组存活时间较其他两组显著延长(P<0.05).单纯移植组移植区可见大量淋巴细胞浸润,主要为CD3+T淋巴细胞;混合移植组移植区Bcl-2基因呈高表达;各组移植区HO-1基因均有表达,差异不明显.结论 NPSCs与大鼠胰岛细胞联合移植可以延长大鼠同种异体胰岛移植物的存活时间,其机制可能与NPSCs抑制移植物淋巴细胞浸润、促进Bcl-2基因高表达的局部免疫调节作用有关.     

结直肠癌恶性程度与吲哚胺2,3-双加氧酶基因表达的关系

目的 探讨吲哚胺2,3-双加氧酶(IDO)基因表达与结直肠癌恶性程度、结直肠癌肝转移、淋巴结转移的关系.方法 对121例结直肠癌肿瘤标本行IDO单克隆抗体免疫组织化学染色,并应用逆转录-聚合酶链反应(RT-PCR)、Western blot测定IDO基因表达水平,观察正常黏膜、癌旁组织、癌组织中IDO的表达,分析IDO基因表达与结直肠癌肿瘤恶性程度的关系.结果 35.5%(43/121)结直肠癌组织中存在IDO基因表达,且癌组织比癌旁组织和正常黏膜明显上调.肿瘤细胞为低/未分化者、结直肠癌伴有淋巴结转移和肝转移者,IDO阳性表达率高达61.1%、65.3%和87.5%,且半数以上为强阳性(+++)表达.结论 结直肠癌组织中IDO酶表达上调与肿瘤的恶性程度密切相关,可以作为结直肠癌手术预后的一种判断指标.在晚期结直肠癌及伴有淋巴结或肝转移时IDO基因高表达,提示IDO酶催化的局部色氨酸代谢可能参与肿瘤免疫逃避微环境的形成.     

IDO与胆囊癌的免疫耐受

吲哚胺2,3双加氧酶(IDO)是色氨酸沿犬尿酸途径分解代谢的限速酶,其高表达是导致肿瘤免疫耐受的原因之一,直接影响树突状细胞(DC)疫苗的肿瘤治疗效果.脂多糖和细胞凶子等物质可调节IDO的表达.IDO通过3种机制参与肿瘤局部免疫耐受.对IDO的这种免疫调节机制的深入研究将在胆囊癌等肿瘤治疗方面具有重大意义.     

1，25-（OH）2D3的免疫抑制作用及其在器官移植中的应用（文献综述）

近年的研究证实1，25-(OH)2D3具有重要的免疫调节作用，可以调节细胞因子的产生，抑制移植物急性排斥反应，延长移植物生存期。本文就1，25-(OH)2D3免疫调节作用的分子生物学机制、对免疫活性细胞的调节作用及其在器官移植后预防急性排斥反应中的作用等方面的研究进展作一综述。     

吲哚胺2,3双加氧酶在诊断肝移植急性排斥中的作用

目的 探讨外周血吲哚胺2,3双加氧酶(IDO)基因表达对大鼠肝移植急性排斥反应(AR)的诊断价值.方法 建立大鼠原位肝移植模型,分为4组:A组:同基因移植组(Wistar-Wistar,n=32);B组:异基因移植组(SD-Wistar,n=32);C组:异基因移植+长期环孢素A组(CsA,n=32);D组:异基因移植+短期CsA组(用药剂量同C组,第3天起停药,n=32).应用实时聚合酶链反应(Real-time PCR)方法 分别检测术后第0、1、2、3、4、5、7、9天外周血IDO mRNA值,同时检测各时间点血清谷草转氨酶(AST)、总胆红素(T-BIL)、碱性磷酸酶(ALP)水平,并取肝脏病理切片.结果 A组外周血IDO mRNA呈持续低水平,AST、T-BIL、ALP逐渐降至正常,病理无排斥反应.C组检测结果 与A组相似.B组IDO mRNA显著上升为术后第2天(P<0.05),AST、T-BIL、ALP值显著上升为术后4d(P<0.01),病理切片判断轻度排斥为术后5d(χ2=4.8,P<0.05).D组IDO mRNA显著上升为术后第4天(P<0.05),AST、T-BIL、ALP值显著上升为术后5d(P<0.01),病理切片判断轻度排斥为术后7d(χ2=4.8,P<0.05).结论 外周血IDO mRNA检测可较病理检查更早诊断大鼠肝移植AR的发生,且方法 简单、安全.

Abstract：

Objective To study the diagnostic value of indoleamine 2, 3-dioxygenase (IDO) gene expression in acute liver rejection in rat orthotopic liver transplantation model. Methods The rat orthotopic liver transplantation models were divided into four groups: group A, isograft transplantation group (Wistar to Wistar); group B, allograft transplantation (SD to Wistar); group C, allograft transplantation and cyclosporine; Group D, allograft transplantation and cyclosporine (the drug was withdrawn on the 3rd day after the operation). The samples (peripheral blood and liver tissue) were obtained on the operation day, 1st, 2nd, 3rd, 4th, 5th, 7th and 9th day post-operation. Luorescent quantitative polymerase chain reaction (PCR), pathological study and serum test were performed on each sample. Results In groups A and C, the IDO mRNA was expressed at a low level, aspartate aminotransferase (AST), total bilirubin (T-BIL) and alkaline phosphatase (ALP) were decreased to the normal level, and the pathological test found no acute rejection (AR). In group B, the IDO mRNA was dramatically increased on the day 2 (P<0.05), AST, T-BIL and ALP rose dramatically on the day 4 (P<0.05), and mild AR was detected on the day 5 (χ2=4.8,P<0.05). In group D, the IDO mRNA was dramatically increased on the day 4 (P<0.05), AST, T-BIL and ALP rose dramatically on the day 5 (P<0.01), and mild AR was detected on the day 7 (χ2=4.8,P<0.05). Conclusion Comparing with pathological study, detecting IDO mRNA of peripheral blood can diagnose AR of rat at earlier stage and the technique is safe and simple.     

Induction of Indoleamine 2,3‐Dioxygenase by Gene Delivery in Allogeneic Islets Prolongs Allograft Survival

Indoleamine 2,3‐dioxygenase (IDO), an enzyme that plays a critical role in fetomaternal tolerance, exerts immunoregulatory functions suppressing T‐cell responses. The aims of this study were to promote IDO expression in rat islets using a nonviral gene transfer approach, and to analyze the effect of the in vivo induction of IDO in a model of allogeneic islet transplantation. The IDO cDNA was isolated from rat placenta, subcloned into a plasmid and transfected into rat islets using Lipofectamine. The efficiency of transfection was confirmed by qRT‐PCR and functional analysis. The in vivo effect of IDO expression was analyzed in streptozotocin‐induced diabetic Lewis rats transplanted with allogeneic islets under the renal capsule. Transplantation of IDO‐allogeneic islets reversed diabetes and maintained metabolic control, in contrast to transplantation of allogeneic nontransfected islets, which failed shortly after transplantation in all animals. Graft survival of allograft islets transfected with IDO transplanted without any immunosuppression was superior to that observed in diabetic rats receiving nontransfected islets. These data demonstrated that IDO expression induced in islets by lipofection improved metabolic control of streptozotocin‐diabetic rats and prolonged allograft survival.     

Nitric oxide and indoleamine 2,3-dioxygenase mediate CTLA4Ig-induced survival in heart allografts in rats

Cytotoxic T lymphocyte-associated antigen 4 immunoglobulin (CTLA4Ig) leads to transplantation tolerance in mice depending on indoleamine 2,3-dioxygenase (IDO). We have shown that CTLA4Ig induces indefinite heart allograft survival in rats and that nitric oxide (NO) was implicated in the in vitro active tolerogenic mechanisms mediated by dendritic cells (DCs). Here we studied the in vivo tolerogenic mechanisms by which CTLA4Ig induces graft survival in rats receiving a cardiac allograft. Treatment of recipients with the IDO inhibitor 1-methyltryptophan (1-MT) did not abrogate the indefinite graft survival observed with CTLA4Ig alone. This was also the case after administration of the inducible nitric oxide synthase inhibitor aminoguanidine when again, indefinite allograft survival was maintained. However, administration of both inhibitors led to acute rejection. We show that IDO and NO are responsible for the impaired capacity of DCs from CTLA4Ig-treated rats to stimulate allogeneic T cells. In conclusion, we show that NO and IDO mediate CTLA4Ig-induced tolerance in rat allograft recipients.     

Cigarette smoke exposure hinders long-term allograft survival by suppressing indoleamine 2, 3-dioxygenase expression

Cigarette smoke causes cancer and increases the vulnerability of smokers to infections. Epidemiologic studies have shown that smoking is one of major risk factors for late allograft rejection. Despite statistical data that associate smoking with allograft rejection, no any study has been conducted to prove that cigarette smoke directly causes allograft rejection in a cause-effect manner. In particular, investigation into immunologic mechanisms underlying smoke-related allograft rejection is lacking. Here we found that second hand smoke (SHS) hindered long-term islet allograft survival induced by CD154 costimulatory blockade plus donor-specific splenocyte transfusion (DST), although it failed to alter acute islet allograft rejection. SHS did not directly interfere with vigorously alloreactive T-cell proliferation in vivo and in vitro. Neither naturally occurring nor induced CD4+CD25+ Treg cell numbers were significantly reduced by SHS. However, SHS suppressed mRNA and protein expression of indoleamine 2, 3-dioxygenase (IDO) and its activity upon transplantation while IDO overexpression in islet allografts restored their long-term survival induced by CD154 blockade. Therefore, SHS prevents long-term allograft survival by inhibiting IDO expression and activity. Thus, our study for the first time demonstrates that SHS shortens allograft survival in a cause-effect manner and unveils a novel immunologic mechanism underlying smoking-related allograft rejection.     

Non-invasive monitoring of kidney allograft rejection through IDO metabolism evaluation

The immunomodulatory enzyme indoleamine 2,3-dioxygenase (IDO) is activated by interferon-gamma (IFN-gamma) and via tryptophan depletion, suppresses adaptive T cell-mediated immunity in inflammation, host immune defense, and maternal tolerance. Its role in solid organ transplantation is still unclear. Therefore, we investigated the usefulness of IDO-mediated tryptophan catabolism in the evaluation of kidney allograft rejection. Blood, urine, and tissue samples were collected from 34 renal transplant patients without rejection and from nine patients with biopsy-confirmed episodes of acute rejection (n=12). Concentrations of kynurenine and tryptophan in serum and urine were analyzed by high-pressure liquid chromatography. Kynurenine to tryptophan ratio (kyn/trp) was calculated to estimate IDO activity. Immunostaining for IDO was performed on renal biopsies. Neopterin was assessed using radioimmunoassay. Kyn/trp and neopterin were detectable at low levels in serum of healthy volunteers and were increased in non-rejecting allograft recipients. Serum levels of kyn/trp were higher in recipients with rejection compared to non-rejectors as early as by day 1 post-surgery. Rejection episodes occurring within 13+/-5.9 days after transplantation were accompanied by elevated kyn/trp in serum (114+/-44.5 micromol/mmol, P=0.001) and urine (126+/-65.9 micromol/mmol, P=0.02) compared to levels during stable graft function. Kyn/trp correlated significantly with neopterin suggesting an IFN-gamma-induced increase in IDO activity. Immunostaining showed upregulation of IDO in rejection biopsies, localized in tubular-epithelial cells. Non-rejected grafts displayed no IDO expression. Acute rejection is associated with simultaneously increased serum and urinary kyn/trp in patients after kidney transplantation. Thus, IDO activity might offer a novel non-invasive means of immunomonitoring of renal allografts.     

Canine small bowel transplantation. A study of the immunological responses.

A canine small bowel allograft model was used to determine the effects of radiation to the graft in modifying the immunological effects of the passenger leukocytes. When untreated allografts were transplanted, death of the recipient animals occurred at a mean of nine days. The allograft was well-preserved and showed no signs of rejection. The reasons for attributing death to graft-versus-host (GVH) disease are discussed. When allografts were treated with 150 rads prior to transplantation, allograft rejection occurred, with death of the recipient animals at a mean of 9.2 days. This was the only group in which cell-mediated immunity developed. When allografts were treated with 50 rads, prolonged survival of the recipients to a mean of 28 days was noted. It is postulated that in this group a balance was struck between the allograft rejection reaction and GVH disease, with prolongation of allograft survival.     

Delayed function reduces renal allograft survival independent of acute rejection

BACKGROUND: Mechanisms by which delayed allograft function reduces renalallograft survival are poorly understood, This study evaluatedthe relationship of delayed allograft function to acute rejectionand long-term survival of cadaveric allografts. METHODS: 338 recipients of cadaveric allografts were followed until death,resumption of dialysis, retransplantation, loss to follow-up,or the study's end, whichever came first. Delayed allograftfunction was defined by dialysis during the first week followingtransplantation, Multivariate Cox proportional hazards survivalanalysis was used to assess the relationship of delayed allograftfunction to rejection and allograft survival. RESULTS: Delayed allograft function, recipient age, preformed reactiveantibody levels, prior kidney transplantation, recipient race,rejection during the first 30 days and rejection subsequentto 30 days following transplantation were predictive of allograftsurvival in multivariate survival models. Delayed allograftfunction was associated with shorter allograft survival afteradjustment for acute rejection and other covariates (relativerate of failure [RR]=1.72 [95% CI, 1.07, 2.76]). The adjustedRR of allograft failure associated with any rejection duringthe first 30 days was 1.99 (1.23, 3.21), and for rejection subsequentto the first 30 days was 3.53 (2.08, 6.00). The impact of delayedallograft function did not change substantially (RR=1.84 [1.15,2.95]) in models not controlling for acute rejection. Theseresults were stable among several subgroups of patients andusing alternative definitions of allograft survival and delayedallograft function. CONCLUSIONS: This study demonstrates that delayed allograft function andacute allograft rejection have important independent and deleteriouseffects on cadaveric allograft survival. These results suggestthat the effect of delayed allograft function is mediated, inpart, through mechanisms not involving acute clinical rejection.     

Intragraft CD11b+IDO+ Cells Mediate Cardiac Allograft Tolerance by ECDI‐Fixed Donor Splenocyte Infusions

We have previously shown that pre‐ and post‐transplant infusions of donor splenocytes treated with 1‐ethyl‐3‐(3’‐dimethylaminopropyl)‐carbodiimide (ECDI‐SPs) provide permanent donor‐specific protection of islet allografts. The efficacy of donor ECDI‐SPs in protecting vascularized cardiac allografts and mechanism(s) of protection are unknown. In this study, we show that infusions of ECDI‐SPs significantly prolong cardiac allograft survival concomitant with an impressive accumulation of CD11b⁺IDO⁺ cells in the cardiac allograft, and that the presence of this population is dependent on Gr1⁺ cells. Consequently, depletion of Gr1⁺ cells or inhibition of indoleamine 2,3 dioxygenase (IDO) activity abrogates graft protection by ECDI‐SPs infusions. In addition, T cells from ECDI‐SPs treated recipients secrete high levels of interleukin 10 and interleukin 13 upon in vitro restimulation, which are also dampened in recipients treated with the IDO inhibitor. Furthermore, combination of donor ECDI‐SPs with a short course of rapamycin provides indefinite cardiac allograft survival in 100% of the recipients. These findings reveal a novel mechanism of donor ECDI‐SPs in inducing cardiac transplant tolerance and provide several targets that are amenable to therapeutic manipulations for tolerance induction for cardiac transplantation.     

Effect of mixed hematopoietic chimerism on cardiac allograft survival in cynomolgus monkeys

BACKGROUND: We have previously reported the successful induction of mixed chimerism and long-term acceptance of renal allografts in MHC-mismatched nonhuman primates after nonmyeloablative conditioning and donor bone marrow transplantation. In this study, we extended our regimen to cardiac allotransplantation and compared the immunological responses of heart and kidney allograft recipients. METHODS: Five cynomolgus monkeys were conditioned with low-dose total body irradiation (1.5 Gy on days -6 and -5), supplemental thymic irradiation (7 Gy on day -1), antithymocyte globulin (50 mg/kg on days -2, -1, and 0), splenectomy (day 0), donor bone marrow transplantation (day 0), and a 4-week posttransplant course of cyclosporine. Heart allografts from MHC-mismatched donors were transplanted heterotopically on day 0. RESULTS: Two monkeys failed to develop multilineage chimerism and rejected their allografts soon after cyclosporine was stopped (postoperative days [PODs] 43 and 56). Three monkeys developed multilineage chimerism, which persisted 20 to 43 days posttransplant by flow cytometric analysis and to POD 124 by polymerase chain reaction analysis. Allograft survival in these recipients was prolonged to 138, 428, and 509 days, and in vitro mixed leukocyte reaction and cell-mediated lympholysis (CML) assays demonstrated donor-specific hyporesponsiveness. However, in contrast to kidney allograft recipients, long-term heart allograft recipients eventually developed humoral and cellular immunity against the donor and rejected the grafts. At the time of rejection, 1.3% to 9.5% of donor coronary arteries exhibited intimal proliferation. CONCLUSIONS: The induction of transient mixed hematopoietic chimerism leads to long-term heart allograft survival in MHC disparate monkeys without chronic immunosuppression. However, unlike kidney allografts, full tolerance to cardiac allografts was not achieved. Organ-specific modifications of the preparative regimen may be necessary to prevent the chronic cellular and humoral immune responses elicited by cardiac allografts.     

Why do preemptive kidney transplant recipients have an allograft survival advantage?

BACKGROUND: Preemptive kidney transplantation is associated with an allograft survival advantage and is promoted in part because of this association. The basis for the allograft survival advantage in preemptive recipients is unclear. Possibilities include a lead time bias due to the earlier transplantation of patients with preserved native kidney function, less rapid loss of kidney function after transplantation, or the longer patient survival of preemptive recipients. METHODS: We compared the glomerular filtration rate (GFR) six months after transplantation and the subsequent rate of loss of kidney function as defined by the annualized change in GFR (mL/min/1.73 m2/year) in 5,966 preemptive and 34,997 non-preemptive recipients. Linear regression methods were applied to serial GFR estimates after transplantation to determine the annualized change in GFR. Multiple regression was used to determine the independent effect of preemptive transplantation upon the annualized change in GFR. RESULTS: The mean GFR six months after transplantation was similar among preemptive (49.5+/-15.7 mL/min/1.73 m2) and non-preemptive (49.2+/-14.7 mL/min/1.73 m2) recipients (P=0.37). In multivariate analysis, preemptive recipients had a slower decline in GFR (0.28 mL/min/year/1.73 m2; 95% confidence interval 0.11, 0.46; P=0.002). However, this difference was of modest clinical significance and would not explain the allograft survival advantage of preemptive transplantation. CONCLUSIONS: Neither the preservation of native kidney function nor differences in the rate of loss of kidney function explain the superior allograft survival of preemptive recipients. By exclusion, the allograft survival advantage associated with preemptive transplantation may be due to the longer survival of preemptive recipients.