Cytochrome P450 3A4 and P-glycoprotein Activity and Assimilation of Tacrolimus in Transplant Patients with Persistent Diarrhea

Renal transplant recipients suffering from persistent diarrhea have been repeatedly reported to have increased tacrolimus (Tac) trough levels. This study aimed to explore this phenomenon in detail in 15 renal transplant recipients with diarrhea, whose immunosuppression consisted of corticosteroids, mofetil mycophenolate and Tac. Both hepatic and intestinal CYP3A4 and PGP activity, important determinants of Tac bioavailability, were assessed, together with global CYP activity and investigations for gastrointestinal infection, function and morphology. Global CYP, CYP3A4, PGP and trough/dose levels of Tac were compared with diarrhea-free controls. In addition, a pharmacokinetic study of Tac was performed in 11 patients affected by diarrhea versus 9 controls. As expected, diarrhea was associated with increased Tac trough levels. An even stronger, significant increase of dose-normalized Tac levels was observed between 90 and 360 min after Tac intake. Time to peak concentration and drug half-life, however, were not altered. In addition, a concomitant decrease (+/-50%) of intestinal PGP activity was noticed in patients with diarrhea. For global CYP, CYP3A4 and hepatic PGP activity no such differences were noted. This pattern was not influenced by the specific cause of diarrhea. These data strongly suggest that persistent diarrhea is associated with an increased oral bioavailability of Tac.     

Lymphoid Neogenesis in Murine Cardiac Allografts Undergoing Chronic Rejection

Lymphoid neogenesis is the process by which ectopic lymphoid accumulations that resemble lymph nodes arise in nonlymphoid tissues. Such lymphoid accumulations, known as tertiary lymphoid organs (TLO), are observed in chronic autoimmunity and they propagate immune pathology by setting up local antigen presenting sites. Whether lymphoid neogenesis occurs in transplanted organs and contributes to rejection is not well understood. To begin to address this question, we retrospectively analyzed 319 murine cardiac allografts for microscopic evidence of lymph-node-like structures. We found 78 allografts that had either classical TLO, characterized by discrete T- and B-cell zones and high endothelial venules (HEV) expressing peripheral node addressin (PNAd) (n = 34), or PNAd(+) HEV without organized lymphoid accumulations (n = 44). These changes were present in both short- and long-lived allografts and were invariably associated with rejection. Importantly, they occurred in 78% of allografts undergoing chronic rejection (n = 85) but in only 7% of allografts undergoing primarily acute rejection (n = 184). These findings indicate that, like autoimmunity, alloimmunity is associated with lymphoid neogenesis in the target organ and suggest a role for local T-cell activation in chronic allograft rejection.     

神经干细胞静脉移植治疗脊髓损伤的实验研究

[目的]观察神经干细胞静脉移植对损伤大鼠脊髓功能的治疗作用。[方法]取孕14—16dSD胎鼠的脑室下区组织，体外培养后鉴定细胞。制作脊髓全切模型，伤后1周将Brdu标记好的神经干细胞通过尾静脉注射移植到大鼠体内，移植后及8周行皮层体感诱发电位（CSEP）检测和BBB功能评分，并留损伤脊髓处作病理切片及免疫组化染色。[结果]（1）移植后8周BBB评分损伤组、移植组都有所恢复，但都未达到正常水平，移植组恢复较好；（2）模型制作后，CSEP波均消失，细胞移植后8周移植组的波形有不同程度的恢复，但潜伏期延长；（3）移植组大鼠脊髓损伤处存在大量Brdu染色阳性细胞，表明移植的细胞在体内可到达损伤脊髓处并能存活；脊髓损伤部位NF-200及GFAP染色阳性的细胞表明移植的细胞可以分化为具有神经元和胶质细胞特性的细胞。[结论]静脉移植的神经干细胞能到达损伤区代替受损的神经元及神经胶质细胞，使损伤的脊髓功能得到一定程度的恢复。     

The Broad Spectrum of Quality in Deceased Donor Kidneys

The quality of the deceased donor organ clearly is one of the most crucial factors in determining graft survival and function in recipients of a kidney transplant. There has been considerable effort made towards evaluating these organs culminating in an amendment to allocation policy with the introduction of the expanded criteria donor (ECD) policy.
Our study, from first solitary adult deceased donor transplant recipients from 1996 to 2002 in the National Scientific Transplant Registry database, presents a donor kidney risk grade based on significant donor characteristics, donor–recipient matches and cold ischemia time, generated directly from their risk for graft loss. We investigated the impact of our donor risk grade in a naïve cohort on short- and long-term graft survival, as well as in subgroups of the population.
The projected half-lives for overall graft survival in recipients by donor risk grade were I (10.7 years), II (10.0 years), III (7.9 years), IV (5.7 years) and V (4.5 years). This study indicates that there is great variability in the quality of deceased donor kidneys and that the assessment of risk might be enhanced by this scoring system as compared to the simple two-tiered system of the current ECD classification.     

调节性CD4+T细胞在大鼠自发肝移植耐受中的作用

目的 探讨在肝移植的自发耐受模型中，调节性CD4^＋T细胞的免疫抑制作用机制。方法 利用近交系大鼠从Lewis（LEW）到Wistar Furth（WF）的肝移植组合，对移植后不同时期的宿主注射抗CD4的单克隆抗体（Anti-CD4mAb），然后抽血检测丙氨酸氨基转氨酶（ALT）的动态变化；并结合细胞毒性T淋巴细胞（CTL）试验了解宿主脾细胞中T细胞亚群的动态改变。结果 对肝移植自然生存的宿主注射Afiti—CD4mAb后，术后第21天、42天均能够诱导出肝损害（排斥反应），但第56天、100天以上的则未能诱导出来，且该损害能被抗CD8单克隆抗体阻断。另外CTL试验显示宿主的脾细胞中，初始型CTL前体细胞在移植56d后未能检测出来。结论 在自发性肝耐受模型中。宿主术后早期存在由CD4^＋T细胞介导的下调原始效应性T细胞的作用机制。     

Presence of beta human papillomaviruses in nonmelanoma skin cancer from organ transplant recipients and immunocompetent patients in the West of Scotland

Background  Nonmelanoma skin cancer (NMSC) has been linked to cutaneous human papillomaviruses of the genus beta (betaPV).
Objectives  We sought to assess the presence of betaPV in NMSC biopsies from a group of Scottish skin cancer patients, both immunocompetent (IC) patients and immunosuppressed (IS) organ transplant recipients.
Methods  One hundred and twenty-one paraffin-embedded skin tumours (27 actinic keratosis, 41 intraepidermal carcinoma, 53 squamous cell carcinoma) and 11 normal skin samples were analysed for the presence of betaPV by a polymerase chain reaction–reverse hybridization assay designed to detect the presence of the 25 known betaPV genotypes.
Results  In IC patients, betaPV was detected in 30 of 59 (51%) tumours and two of 11 (18%) normal skin samples ( P  =   0·046). In IS patients, betaPV was found in 27 of 62 (44%) tumours; no normal skin samples were available for comparison. The most frequently found genotypes were HPV-24, HPV-15 and HPV-38. Of those tumours infected with betaPV, 28 of 57 (49%) were infected with more than one genotype (range 2–8). Tumours from IS patients were from a younger age group (mean age 57·4 years) than IC patients (mean age 73·8 years). Multiple infections were more common in tumours from IC patients (21 of 30; 70%) compared with those from IS patients (seven of 27; 26%) ( P  <   0·001). In the IC group, age did not appear to influence the distribution of single and multiple infections whereas in IS patients the proportion of multiple infections to single infections increased with age. There were no multiple infections in normal skin.
Conclusions  A wide spectrum of betaPV types was detected in our samples. Further characterization of betaPV in vivo is needed in order to determine the mechanisms by which the virus contributes to cutaneous carcinogenesis.     

A new strategy of delayed long-term prophylaxis could prevent cytomegalovirus disease in (D+/R−) solid organ transplant recipients

Abstract:  Long-term prophylaxis against cytomegalovirus (CMV) started immediately after transplantation in (D+/R−) poses a higher risk of late-onset CMV disease. Delayed CMV prophylaxis could allow a transitory exposure of the immune system to CMV, which would let the immune system mount an adequate CMV-specific cytotoxic response in (D+/R−) patients and confer protection against CMV disease. We included all (D+/R−) solid organ transplant recipients (SOT) performed at our institution (January 3/October 6) who received CMV prophylaxis (mainly with oral valganciclovir) during 100 d. In the first period (until December 4), prophylaxis was initiated immediately after transplantation (conventional prophylaxis: CP). Since January 5, it was initiated after 14 d (delayed prophylaxis: DP). Incidence and severity of CMV disease was compared between both groups. A total of 44 SOT recipients were included (CP: 26 and DP: 18). CMV disease was diagnosed in eight patients (18%), seven of 26 (27%) in the CP group, and one of 18 (5.5%) in the DP group (p = 0.07). CMV colitis was reported in five of 26 patients in the CP group (19%), whereas there were no cases of visceral CMV disease in the DP group (p = 0.048). A 14-d delay in the beginning of long-term prophylaxis against CMV in (D+/R−) is safe and could prevent the onset of late-CMV disease.     

Cytomegalovirus infection and disease in the new era of immunosuppression following solid organ transplantation

Abstract: As the most prevalent pathogen among transplant patients, cytomegalovirus (CMV) affects up to three-quarters of all solid organ transplant recipients. While we have made great strides in preventing CMV infection and disease in the early post-transplant period, late CMV infection and indirect effects due to viral immunomodulation remain problematic. Changing immunosuppression practices, including the increasing use of T-cell depleting induction antibodies, have the potential to affect the risk for CMV infection and disease, even in the face of good prophylactic and preemptive therapy. The purpose of this review article is to discuss the impact of CMV infection on long-term allograft outcomes and to re-evaluate the risks and management strategies for prevention of CMV in the framework of evolving modern immunosuppressive strategies.     

Prior diabetes mellitus is associated with increased morbidity in cystic fibrosis patients undergoing bilateral lung transplantation: an ‘orphan’ area? A retrospective case–control study

Background: The aim of this study was to determine whether pre-existing diabetes mellitus increases the risk of rejection, infection and/or death in cystic fibrosis patients undergoing bilateral sequential single-lung transplantation.
Methods: A retrospective audit of 25 consecutive patients with cystic fibrosis who underwent bilateral sequential single-lung transplantation between 1 January 2003 and 31 December 2005 at a tertiary referral hospital was carried out.
Results: Although 32% patients had diabetes diagnosed before lung transplantation, 92% had random blood glucose levels ≥11.1 mmol/L requiring insulin during admission. Patients with pre-existing diabetes had increased infection-related (3.9 vs 1.2, P = 0.01) and putative rejection-related (1.4 vs 0.5, P = 0.04) hospital admissions post-transplantation compared with those without diabetes pre-transplant. During the period of observation, four of eight patients with a prior diagnosis of diabetes died compared with none of 17 patients without prior diabetes ( P = 0.0055).
Conclusion: Almost all cystic fibrosis patients develop hyperglycaemia after lung transplantation, but patients with prior diabetes have more complication-related admissions to hospital and a higher mortality rate.