Immunologic benefits of longer graft in rat allogenic small bowel transplantation

BACKGROUND: The effect of graft length on rejection reaction in small bowel transplantation (SBT), which is poorly understood, is tested using rat allogenic SBT models with a short course of tacrolimus. MATERIALS AND METHODS: Inbred Brown Norway rats (major histocompatibility complex: RT1) and Lewis rats (RT1) were used as donors and recipients, respectively. The intestinal tract of the recipient was partially or totally replaced by segmental (15 cm) or whole (70 cm) donor intestine, using two different SBT models. With tacrolimus treatment (0.64 mg/kg per day, 0-13 postoperative days, intramuscularly), recipients' body weights and their survival were evaluated. To compare the extent of peripheral chimerism, donor passenger leukocytes were followed using flow cytometry with a donor-specific monoclonal antibody, OX-27. For the periodical histologic analysis, heterotopic SBT and protocol biopsies of the graft were also performed with short or long intestinal grafts. RESULTS: In a classical Monchik and Russell orthotopic SBT model, whole SBT recipients survived more than 60 days. However, all of the allogenic segmental SBT recipients died within 14 days without histologic sign of graft rejection. In the modified orthotopic SBT model using a cuff technique without systemic clamping, all recipients with segmental allograft survived longer than 29 days. However, recipients with whole graft tended to survive longer than those with segmental graft. The suffering period, lasting from the onset of rejection to death, was significantly shorter in the segmental group than in the whole group. Flow cytometric analysis showed that recipients with whole intestinal grafts had significantly higher ratio of donor passenger leukocytes in peripheral blood. Histologic studies of the protocol biopsies showed that the shorter graft tended to be more severely rejected than the longer graft. CONCLUSIONS: We have demonstrated experimentally that long intestinal grafts have immunologic advantage over short grafts.     

The association of viral infection and chronic allograft nephropathy with graft dysfunction after renal transplantation

BACKGROUND: The long-term effect of viral infections on graft dysfunction and rejection after renal transplantation is uncertain. METHODS: A cohort of 37 renal transplant recipients was followed prospectively for 3 years. Creatinine clearance rate at 6 months and 3 years and chronic allograft nephropathy were correlated with the detection of cytomegalovirus (CMV), human herpesvirus 6 and human herpesvirus 7 and BK virus DNA, CMV disease, and acute rejection. RESULTS: CMV disease was significantly associated with poor graft function at 6 months, whereas chronic allograft nephropathy was associated with graft dysfunction at 3 years. Both CMV disease and detection of human herpesvirus 6 DNA were associated with chronic allograft nephropathy. CONCLUSIONS: CMV disease was a significant cause of early graft dysfunction, whereas the presence of chronic allograft nephropathy was the main determinant of poor long-term graft function. The role of viral infections in chronic allograft nephropathy deserves further investigation.     

Influence of cytomegalovirus disease on early and late renal graft function

The role of cytomegalovirus (CMV) disease to induce chronic nephropathy using new immunosuppressive regimens is debated. This study sought to assess the influence of CMV disease on early and late graft function in relation to immunosuppressive therapy. Among 456 renal recipients transplanted from 1997 to 2003, 95 were diagnosed with CMV disease on the basis of clinical symptoms and the presence of pp65 protein. The patients were divided into 2 groups according to their immunosuppressive regimen: group I included 43 patients treated with cyclosporine (CsA), azathioprine (AZA), and prednisone (P); group II, 52 patients treated with calcineurin inhibitor (CI), mycophenolate mofetil (MMF), and P. A control group of 90 CMV disease-free renal recipients were transplanted in 2001. CMV disease occurred in 20.8% of renal recipients: 14.8% from group I and 25.5% from group II. CMV disease was diagnosed in 73 patients (76.8%) before the third month after transplantation. An acute rejection episode (ARE) appeared in 42 patients, of whom 31 had CMV disease diagnosed within 1 month after ARE, while 5 before an ARE. In six patients ARE was not time related to CMV disease. The serum creatinine values at 6 months after transplantation were significantly higher among the CMV versus control groups: 1.69 and 1.76 vs 1.49 (P < .05). In patients with ARE and CMV disease, the serum creatinine value was also higher at 6 and 12 months after transplantation compared with patients without an ARE (P < .03). One- and 3-year graft survival rates were 95.1% and 83.7% in group I versus 93.4% and 86.5% in group II versus 95.4% and 90.2% in the control group. In conclusion, CMV disease showed a negative impact on early graft function independent of the immunosuppressive regimen, an effect that was emphasized by an ARE.     

Impact of presence of HBs antigen and anti-hepatitis C virus and anti-cytomegalovirus antibodies on transplanted kidney survival

INTRODUCTION: Infections are one of the most common complications after organ transplantation. Viral infections such as hepatitis type B (HBV) and C (HCV) or cytomegalovirus (CMV) infections are among the most serious ones. A high frequency of HBV and HCV infections has been recognized in kidney recipients. Viral infections play a special role in graft recipients because of clinical symptoms influencing graft function and recipient survival. Immunosuppressive treatment to decrease immunological reactions after organ transplantation may increase the risk of viral infections. The aim of this study was to evaluate the impact of the presence of HBs antigen and HCV and CMV antibodies on patient and graft survivals. MATERIAL AND METHODS: Two hundred one enrolled kidney transplantation patients (96 women and 105 men) were treated with the same immunosuppressive regimen. Age, sex, and viral state (HBs antigen, anti-HCV and anti-CMV antibodies) were evaluated in every patient. Statistical analysis was performed with the Gompertz model, Kaplan-Meier curves and Cox proportional hazard tests. RESULTS: The presence of HBs antigen was detected in 161 patients (20.4%), HCV antibodies in 61 recipients (30.3%); and CMV antibodies in 12 patients (5.9%). Eighty-seven recipients (43.4%) were seronegative. Average recipient age was 38.5 years. CONCLUSION: Time of graft function was independent of the presence of HBs antigen or HCV or CMV antibodies.     

Viral infection following kidney transplantation: long-term follow-up in a single center

INTRODUCTION: Viral infections are a leading cause of posttransplantation morbidity and mortality. The use of more potent immunosuppressive agents is responsible in part for the increasing incidence of some viral infections. This study summarized our experience with viral infections in 561 kidney transplant recipients. METHODS: The spectrum of viral infections in 561 consecutive kidney transplant recipients was examined retrospectively from November 1982 to November 2002. RESULTS: During a mean follow-up of 64.0 months, 193 virus infections in 156 of 561 kidney transplant recipients were recorded, an incidence of 34.2%. The most common viruses were cytomegalovirus (36.3%), varicella zoster virus (29.0%), herpes simplex virus (23.8%), BK virus (4.7%), hepatitis B virus (3.6%), and hepatitis C virus (2.6%). Among the CMV infections, 77.1% developed subclinical CMV infection and 22.9% had CMV disease. Generalized herpes zoster infection occurred in three cases and chicken pox in six cases. During a mean follow-up of 64.0 months, two of 159 patients died of CMV pneumonia. CONCLUSION: Viral infections among the kidney transplant recipients continue to be a major problem despite significant progress in understanding the pathogenesis of viral infection and the advent of antiviral therapy.     

Outcome analysis of 71 clinical intestinal transplantations.

OBJECTIVE: The aim of the study was to determine risk factors associated with graft failure and mortality after transplantation of the intestine alone or as part of an organ complex. SUMMARY BACKGROUND DATA: Even with modern immunosuppressive therapies, clinical intestinal transplantation remains a difficult and unreliable procedure. Causes for this and solutions are needed. METHODS: Between May 1990 and February 1995, 71 intestinal transplantations were performed in 66 patients using tacrolimus and low-dose steroids. The first 63 patients, all but one treated 1 to 5 years ago, received either isolated grafts (n = 22), liver and intestinal grafts (n = 30), or multivisceral grafts (n = 11). Three more recipients of allografts who recently underwent surgery and one undergoing retransplantation were given unaltered donor bone marrow cells perioperatively as a biologic adjuvant. RESULTS: Of the first 63 recipients, 32 are alive: 28 have functioning primary grafts and 4 have resumed total parenteral nutrition after graft enterectomy. Thirty-five primary grafts were lost to technical and management errors (n = 10), rejection (n = 6), and infection (n = 19). Regression analysis revealed that duration of surgery, positive donor cytomegalovirus (CMV) serology, inclusion of graft colon, OKT3 use, steroid recycle, and high tacrolimus blood levels contributed to graft loss. All four intestine and bone marrow recipients are alive for 2-3 months without evidence of graft-versus-host disease. CONCLUSION: To improve outcome after intestinal transplantation with previous management protocols, it will be necessary to avoid predictably difficult patients, CMV seropositive donors, and inclusion of the graft colon. Bone marrow transplantation may further improve outcome by ameliorating the biologic barriers of rejection and infection and allowing less restrictive selection criteria.     

The influence of mycophenolate mofetil versus azathioprine and mycophenolic acid pharmacokinetics on the incidence of acute rejection and infectious complications after renal transplantation

PURPOSE: The present retrospective study investigated the influence of mycophenolate mofetil (MMF) instead of azathioprine (AZA) as part of tacrolimus-based immunosuppression. Mycophenolic acid (MPA) pharmacokinetic (PK) parameters were used for associations with the incidence of acute rejection (AR) episodes and infectious complications after renal transplantation. METHODS: The 66 consecutive renal transplant recipients reported herein excluded ABO-incompatible transplants or cytomegalovirus (CMV)-seronegative recipients. The immunosuppressive regimen consisted of tacrolimus, steroids, and AZA 1-2 mg/kg/d in 22 patients (between February 1998 and December 2000) or MMF 2 g/d in 44 patients (since January 2001). CMV infection was defined as positive CMV-antigenemia. MPA PK was studied on day 28 after transplantation in 21 recipients. RESULTS: AR occurred in 13.6% of patients in the MMF group compared with 18.2% in the AZA group. The viral infection (CMV, varicella zoster virus, adenovirus hemorrhagic cystitis, and malignancy related to Epstein-Barr [EB] virus) rate was 22.7% in the MMF group and 0% in the AZA group (P = .015). There were no bacterial or fungal infections observed in the 2 groups. MMF dose per body weight was significantly lower among patients with AR than those without AR (25.1 vs 35.6 mg/kg; P = .026). There were no differences in MPA PK parameters between patients with and without viral infections. CONCLUSIONS: Patients treated with MMF required less treatment for AR, however, there were no significant differences. MMF dose per body weight may play an important role in the occurrence of AR. Although virus infections occurred in recipients treated with MMF, MPA PK did not influence the infectious complications after renal transplantation.     

Soluble interleukin-2 receptor level as an indicator of liver allograft rejection

We studied the serum levels of soluble interleukin-2 receptors (SIL-2R) in liver allograft recipients: a control group without rejection or CMV disease, a group with only rejection episodes, and a group with only cytomegalovirus disease. Rejection was diagnosed by the presence of compatible laboratory and histologic abnormalities and absence of other causes of graft dysfunction. CMV disease was diagnosed by isolation of CMV in blood or liver specimen cultures or identification of cytomegalic inclusions in the liver biopsy specimen. Of 82 consecutive recipients treated with cyclosporine and prednisone, 12 were in the control group, 20 in the rejection group, and 5 in the CMV disease group. The remaining 45 had other or multiple complications. In the control group the SIL-2R levels (determined by an ELISA) decreased by a mean of 4% per day after transplantation; in the rejection group the levels increased by a mean of 17% per day in the 10 days prior to the diagnosis of rejection; in the CMV disease group the levels tended to increase prior to the diagnosis of CMV disease. The rejection group had significantly higher SIL-2R levels than the control group at comparable times. Thus, SIL-2R levels were significantly increased at the time of allograft rejection compared with levels in a control group, and recipients with CMV disease had increased levels of SIL-2R but they were not as high as in recipients with rejection episodes.     

Infectious diseases in kidney transplant recipients treated with cyclosporin

Cyclosporin (CYA) is now recognized as an effective immunosuppressant to lead to a marked improvement in graft survival in organ transplant recipients. Although the incidence of infection in the CYA group has been decreased compared with that in the azathioprine group, infectious diseases in 400 kidney transplant recipients treated with CYA were noted in our single center. Treatment strategy for infectious diseases: Antibiotics and/or gamma-Globulin were administered to all recipients with bacterial infections. Aciclovir was added in recipients with herpes simplex virus (HSV) infection or varicella zoster virus (VZV) infection. Human interferon-beta (HuIFN-beta) was used in recipients who had life-threatening viral infection, especially cytomegalovirus (CMV) pneumonitis. Glycyrrhizin was used for acute hemorrhagic cystitis and nephropathy due to adenovirus (AV). Trimethoprim sulfamethoxazole and/or pentamidine were added in recipients complicated with Pneumocystis carinii (Pc) pneumonitis or in order to prevent Pc pneumonitis. Infectious diseases: One hundred and six recipients had infectious diseases 129 times in this series, seventy-six percent of all infections occurred during the first 4 months after the transplantation. Urinary tract infection (UTI), herpes zoster and pulmonary infection were the most common infectious diseases, occurring in 28.7%, 24.0% and 23.2%, respectively. Septicemia or bacteremia developed in 9 recipients, secondary to UTI in 8 and to surgical wound infection in one. Sixty-one symptomatic viral infections occurred in 57 recipients. A total of 5 recipients (1.3%) died of interstitial pneumonitis. Infectious organisms: Viral and bacterial infections were most common, occurring in 47.3% and 41.9%, respectively. Viral species detected in these recipients with the frequency were HSV 14 times, CMV 9 times, VZV 31 times and AV 7 times. 1) The incidence of viral infections in kidney transplant recipients treated with CYA is relatively high compared to bacterial infections. 2) HuIFN-beta therapy is effective in the treatment of serious opportunistic herpes virus infections, especially CMV pneumonitis. 3) Glycyrrhizin therapy is effective in the treatment of acute hemorrhagic cystitis and nephropathy due to AV and hepatic dysfunction. 4) Aerosolised pentamidine therapy is very useful for prophylaxis of Pc pneumonitis.     

Cytomegalovirus as a risk factor in living-related renal transplantation. A prospective study.

Forty-four living-related donor kidney (LRD) recipients (19 HLA-identical and 25 haploidentical) were followed prospectively to determine the posttransplant incidence and sequelae of cytomegalovirus (CMV) infection as they relate to the CMV status of recipients and donors. CMV titers were measured in all patients before transplantation by an immunofluorescent assay (IFA). Recipients similarly had CMV titers measured at selected intervals after transplant and during febrile episodes. Appropriate viral cultures were simultaneously performed. Laboratory evidence of infection was correlated with symptoms and signs of active CMV disease. Mean follow-up period was 20 +/- 12 months with a range of 3-51 months. Three patients were excluded due to early acute rejection resulting in graft loss. Twenty-eight of 41 donors (68%) and 22 of 41 recipients (54%) had positive CMV titers before transplantation. Six of 41 recipients (15%) subsequently developed clinical and laboratory evidence of CMV infection: three of 19 seronegative recipients and three of 22 seropositive recipients. All six patients received kidneys from seropositive donors. Four patients had severe CMV disease (2 seronegative, 2 seropositive), whereas two patients had leukopenia and fever only. Two patients with severe CMV infections subsequently lost their grafts due to unrelated causes. Overall, actual patient and graft survival of the entire group is 95% and 82%, respectively. In conclusion, individuals who receive LRD kidneys from seronegative individuals are unlikely to develop CMV infection, and transplantation of seropositive LRD kidneys may be associated with transmission of CMV in susceptible recipients regardless of their serologic status. With appropriate management of CMV illness in the posttransplant period, LRD kidney donation is safe and efficacious and should not be discouraged on the basis of pretransplant CMV serology in any donor-recipient pairing.     

Clinical validation of a novel enzyme‐linked immunosorbent spot assay‐based in vitro diagnostic assay to monitor cytomegalovirus‐specific cell‐mediated immunity in kidney transplant recipients: a multicenter,longitudinal, prospective,observational study

Impaired cytomegalovirus (CMV)‐specific cell‐mediated immunity (CMV‐CMI) is a major cause of CMV reactivation and associated complications in solid‐organ transplantation. Reliably assessing CMV‐CMI is desirable to individually adjust antiviral and immunosuppressive therapy. This study aimed to evaluate the suitability of T‐Track^® CMV, a novel IFN‐γ ELISpot assay based on the stimulation of peripheral blood mononuclear cells with pp65 and IE‐I CMV proteins, to monitor CMV‐CMI following kidney transplantation. A prospective longitudinal multicenter study was conducted in 86 intermediate‐risk renal transplant recipients. CMV‐CMI, CMV viral load, and clinical complications were monitored over 6 months post‐transplantation. Ninety‐five percent and 88–92% ELISpot assays were positive pre‐ and post‐transplantation, respectively. CMV‐specific response was reduced following immunosuppressive treatment and increased in patients with graft rejection, indicating the ability of the ELISpot assay to monitor patients' immunosuppressive state. Interestingly, median pp65‐specific response was ninefold higher in patients with self‐clearing viral load compared to antivirally treated patients prior to first viral load detection (P < 0.001), suggesting that reactivity to pp65 represents a potential immunocompetence marker. Altogether, T‐Track^® CMV is a highly sensitive IFN‐γ ELISpot assay, suitable for the immunomonitoring of CMV‐seropositive renal transplant recipients, and with a potential use for the risk assessment of CMV‐related clinical complications (ClinicalTrials.gov Identifier: NCT02083042).     

Infectious enteritis after intestinal transplantation: incidence, timing, and outcome

AIM: To review the incidence, timing, and outcome of infectious enteritis after intestinal transplantation (IT). METHOD: A retrospective review of all patients undergoing IT at a single institution between 1991 and 2003 was analyze with standard statistical tools. RESULTS: Among 33 IT recipients, 13 (39%) developed 20 culture- or biopsy-proven episodes of infectious enteritis. The recipient demographics were 77% men and median age 2.6 years. Infections were diagnosed at a median of 76 days (32 to 1800) after IT. There were 14 viral (CMV one, rotavirus eight, adenovirus four, EBV one, three bacterial (Clostridium difficile), and three other infections (Giardia lamblia one, cryptosporidium two). Complete resolution was achieved in 17 (94%) infectious after appropriate antimicrobial or conservative therapy. Interestingly, there were six rejection episodes following infectious enteritis. Grafts were lost to rejection after rotaviral enteritis (n = 1) and adenoviral enteritis misdiagnosed as rejection (n = 1). Patient and graft survival were not adversely affected by infections. CONCLUSIONS: Infectious enteritis occurs frequently after IT. Viral agents are the cause in two-thirds of cases. With supportive care and appropriate treatment, resolution is possible in the majority of cases. Differentiating rejection and infection by histopathology can be difficult.     

Trophic effect of enteral rehabilitative therapy in rat small bowel transplantation

INTRODUCTION: We aimed to observe the trophic effects on graft structure and recipient metabolism of enteral rehabilitative therapy in rat small bowel transplantation (SBT). METHODS: Forty-eight recipients of rat allogeneic heterotopic SBT (Sprague-Dawley to Wistar rat) were divided into four groups randomly according to the presence of glutamine or growth hormone in the nutritional support regimen. We compared the histologic indices of graft mucosa and metabolic variables, including changes in body weight, nitrogen balance, urinary 3-methyl histidine excretion, and plasma albumin levels during 14 days after transplantation. RESULTS: Glutamine and growth hormone promoted recovery of graft structure and improved recipient protein metabolism, as evidenced by indices of the enteral rehabilitative therapy. CONCLUSIONS: Glutamine and growth hormone potentiated their effects in enteral rehabilitative therapy, which produced potent trophic effects on graft structure and recipient metabolism in rat SBT.     

Evidence that the soluble interleukin 2 receptor level may determine the optimal time for cystoscopically-directed biopsy in pancreaticoduodenal allograft recipients

In 18 consecutive pancreaticoduodenal allograft recipients (15 combined kidney/pancreas and 3 pancreas only after a prior successful kidney transplantation) operated on between December 1987 and February 1989, we studied the soluble interleukin 2 receptor (SIL-2R) level over time. All pancreaticoduodenal allografts were transplanted with exocrine drainage via a duodenocystostomy that allowed for cystoscopically directed needle biopsies of the pancreas. Of these 18 recipients, at 6 weeks after transplantation, 6 had had no rejection episodes or cytomegalovirus disease (control group), an acute allograft rejection had developed in 7, CMV disease developed in 4, and both rejection and CMV disease developed in 1 by 12 days after transplantation. SIL-2R level increased in all patients during immunosuppressive induction therapy (preoperative mean +/- SE, 1637 +/- 284 U/mL; maximum, 4367 +/- 687 U/mL). After induction therapy, the mean was 2768 +/- 432 U/mL. In all 6 recipients in the control group, SIL-2R level continued to decrease. However, SIL-2R level was significantly higher compared with controls, in those who had CMV disease (levels were increased at a mean of 7 days before diagnosis of CMV disease) and in those who had acute rejection episodes (levels were increased a mean of 7 days before the clinical diagnosis of rejection). Factors that did not cause an increase in SIL-2R level included acute pancreatitis, wound infection, operative procedures, and CsA nephrotoxicity. SIL-2R level can be useful for monitoring pancreaticoduodenal allograft recipients. Increases predict impending rejection or CMV disease, prior to the onset of organ dysfunction. When SIL-2R level increases, we recommend cultures of blood and urine to exclude CMV and pancreaticoduodenal allograft biopsy to confirm early rejection prior to the initiation of potentially dangerous antirejection therapy.     

小肠移植与肠道细菌移位

目的　探讨小肠移植后肠道细菌移位的原因和防治方法。方法　综述小肠移植与肠道细菌移位的相关文献。结果　移植小肠缺血再灌注损伤 ,免疫排斥反应 ,移植物抗宿主病和免疫抑制剂的应用都会导致肠粘膜屏障功能损害 ,肠蠕动和运输功能紊乱 ,肠道内条件致病菌过度生长 ,细菌和毒素向肠外组织器官移位 ,引起受体感染。结论　小肠移植后肠道细菌移位的发生率较高 ,是引起受体感染 ,影响预后的一个主要因素。提高肠移植外科技能 ,缩短缺血保存时间 ,选择性肠道去污 ,改进营养支持和免疫抑制方案 ,有望减少肠移植后细菌移位 ,降低感染并发症 ,提高预后指标。     

Infectious enteritis after intestinal transplantation: incidence, timing, and outcome

BACKGROUND: The study reviews the incidence, timing, and outcome of infectious enteritis (IE) after intestinal transplantation (ITx). METHODS: A retrospective review of all patients who underwent ITx at a single institution between 1991 and 2003 was undertaken using database and medical records. Standard statistical analyses were performed. RESULTS: Of 33 ITx recipients, 13 (39%) developed 20 culture- or biopsy-proven episodes of IE. Recipient demographics included the following: 10 males, median age 34 (10-585) months, 11 liver + intestine grafts, and two isolated intestine grafts. Infections were diagnosed a median of 76 days (32-1,800 days) after ITx. There were 14 viral (one cytomegalovirus, eight rotavirus, four adenovirus, one Epstein-Barr virus), three bacterial (Clostridium difficile), and three protozoal (one Giardia lamblia, two Cryptosporidium) infections. The bacterial infections tended to present earlier than the viral infections, and the most frequent presenting symptom was diarrhea. Complete resolution was achieved in 17 (94%) incidences with the appropriate antimicrobial or conservative therapy. It was interesting that there were seven rejection episodes documented by biopsy at the approximate time of diagnosis of IE. There were two graft losses: one because of adenoviral enteritis and one because of rejection after rotavirus enteritis. Three-year patient survival is 74% with no deaths directly attributable to IE. CONCLUSIONS: IE can occur in 39% of recipients after ITx. Viral agents are the cause in two thirds of the cases. With supportive care and appropriate treatment, resolution is possible in the majority of cases. Differentiating rejection and infection on histopathology can be difficult and relies on cultures and immunostaining.     

Gene transfer to the thymus. A means of abrogating the immune response to recombinant adenovirus.

OBJECTIVE: The authors investigated whether adenoviral gene transfer to the thymus could be accomplished in vivo and whether immunologic unresponsiveness to recombinant adenovirus could be induced by intrathymic inoculation. SUMMARY BACKGROUND DATA: A major barrier to the clinical application of adenovirus-mediated gene therapy for diseases requiring long-lasting gene expression is the immunogenicity of adenoviral vectors, which limits the duration of its effects. In other experimental models, intrathymic inoculation of foreign proteins or cells has proven to be an effective means to induce immunologic tolerance. METHODS: The efficiency of gene transfer to the mouse thymus after direct inoculation of recombinant adenovirus was compared with that of several other vectors. Animals inoculated with adenovirus-infected pancreatic islets into the thymus were tested for unresponsiveness to the virus with a subsequent challenge of adenovirus administered into the liver by intravenous injection. RESULTS: Adenovirus accomplished highly efficient gene transfer to the thymus, unlike plasmid DNA, DNA-liposome complexes, retrovirus, and adeno-associated virus. Adenoviral transgene expression was transient in the thymus of immunocompetent mice but persistent in CD8+ T-cell-deficient and severe combined immunodeficiency (SCID) mice, implicating the role of cytotoxic T lymphocytes in viral clearance. Intrathymic transplantation of syngeneic pancreatic islet cells infected with adenovirus impaired the normal antiviral cytotoxic T-lymphocyte response and prolonged hepatic transgene expression after an intravenous challenge with adenovirus. CONCLUSIONS: Recombinant adenovirus accomplishes highly efficient gene transfer to the thymus in vivo. Intrathymic inoculation of adenovirus-infected islets can be used to induce immunologic unresponsiveness to the adenoviral vector and, potentially, to other proteins that it might be engineered to encode.