The immunosuppressive effect of cholera toxin on rat renal allograft

Immunomodulatory effects of cholera toxin (CT) were investigated in a rat model, and the effects of CT on rat renal allograft (from Lewis rat to WKAH rat) were also examined. The results are: 1) The number of lymphocytes in the thymus, spleen and peripheral blood was remarkably decreased after 7 day administration of CT (0.1 and 0.2 mg/kg/day), but the number of red blood cells and neutrophils was not decreased. 2) CT suppressed mixed lymphocyte reaction (MLR) in a dose dependent fashion, and % suppression reached 97% at the concentration of 10 micrograms/ml. The later the time of addition of CT to MLR, the less became this effect. 3) In the control group, the mean survival time (MST) after transplantation was 8.5 +/- 0.3 (Mean +/- SE) days. CT, given 1 day before transplantation, did not prolong MST. In the group to which CT was given daily for 14 days from the day of transplantation, MST was prolonged with the increase of CT. CT at the dosage of 0.2 mg/kg/day prolonged MST (16.2 +/- 3.2 days) significantly (p less than 0.05), where treated with CT from the 3rd day after transplantation, MST (10.3 +/- 1.3 days) was not significantly prolonged. From the above findings, CT seems to act mainly on the early phase of acute rejection and prolongs rat renal allograft survival.     

Identification of natural suppressor cells in long-term renal allograft recipients.

We have previously reported an abnormal expansion of CD3+Leu7+ (CD57+) large granular lymphocytes in long-term renal allograft recipients. These cells lacked NK activity, T-helper activity and did not respond to T cell mitogens. The following studies were done in order to further define the functional characteristics of these cells. We sorted CD3+Leu7+ T cells from the peripheral blood of 45 recipients (all with good renal allograft function), and found that these cells suppress mixed lymphocyte culture responses and pokeweed mitogen-induced IgG secretion in a non-genetically restricted manner. PWM-induced IgG secretion assays are suppressed by 60-100%, and MLC responses are suppressed by 20-85% at a ratio of 1:10 CD3+Leu7+ cells to responder/effector cells. Supernatants from CD3+Leu7+ cell cultures are also suppressive. On the other hand, unsorted cells and non-CD3+Leu7+ sorted cells either enhance responses or produce less than 10% suppression under the same conditions. Patients who were tested more than once showed a relatively stable percentage and suppressive effect of their CD3+Leu7+ cells over an interval of 6-12 months. These nonspecifically suppressive CD3+Leu7+ large granular lymphocytes are similar in many ways to the natural suppressor cells that have been identified in hematopoietic tissues, in graft-vs.-host disease, and in the lymphoid organs of neonates.     

不同免疫抑制方案对肾移植受者和移植肾存活的影响

目的回顾单中心近28年肾移植受者资料,分析探讨不同免疫抑制方案对移植受者和移植肾存活的影响。方法1977年10月至2004年12月,中国人民解放军总医院总共为1804例终末期肾病患者施行了2037例肾移植手术。根据临床资料和截止2005年底的随访结果,采用Kaplan-Meier方法计算人、肾存活率,并按照Terasaki公式计算移植物的半数生存期,分析各种免疫抑制方案对移植肾和移植受者存活的影响。结果以钙调素抑制剂（CNI）为基础的免疫抑制药物治疗显著提高了移植受者和移植肾的存活率,术后1、5、10和15年受者存活率分别为95．9％、89．1％、80．5％和73．0％;移植肾存活率分别为92．7％、80．4％、64．9％和54．1％。与无CNI类药物治疗相比,受者和移植肾的同期存活率差异具有统计学意义（均P〈0．0001）。在CNI为基础的三联药物治疗方案中,采用环孢素＋霉酚酸酯＋泼尼松方案者移植肾1、5、10年存活率高于采用环孢素＋硫唑嘌呤＋泼尼松方案者（1年94．3％比86．4％,5年90．9％比70．6％,10年71．3％比56．5％,均P〈0．0001）。结论以CNI为基础的三联药物治疗方案显著改善了肾移植受者和移植物的存活,特别是以他克莫司为基础的或包含霉酚酸酯的治疗方案对改善肾移植受者和移植物的存活具有重要作用。     

The in vivo immunosuppressive action of suppressor cells from alloantigen-cyclosporine-treated mice and the capacity of spleen cells to release interleukins and gamma-interferon

Antigen-nonspecific suppressor T cells were identified in spleens of mice rendered unresponsive by sensitization of allogeneic antigen in combination with cyclosporine (CsA) treatment. Suppressor cells were obtained from C57BL/6 (B6, H-2b) mice treated with a single i.p. injection of 1 x 10(7) allogeneic P815 (H-2d) cells combined with a five-day course of CsA, a group that did not show any cytotoxic activity of spleen cells against P815 targets. These noncytolytic spleen cells displayed suppressor activity on the induction of cytotoxic T (Tc) cells of normal lymphocytes against not only P815 stimulator (80.9% suppression, P less than 0.01, responder:additional cell ratio = 2.5:1) but also third-party BW5147 (H-2k) stimulator (68.2% suppression, P less than 0.01). The unresponsive state appears to be due to suppressor T (Ts) cells that are nonadherent to plastic or nylon-wool, 1500 rads-sensitive, and Thy-1-positive. Capacities of spleen cells from CsA-P815-treated mice to release cytokines (interleukin 1 [IL-1]), interleukin 2 [IL-2], interleukin 3 [IL-3], and gamma-interferon [gamma-IFN]) were examined. Spleen cells from CsA-P815-treated B6 mice displayed 84.1%, 91.7% and 90.8% inhibition (0.35 +/- 0.07 U/ml, 1.4 +/- 0.29 U/ml, and 7.0 +/- 0.9 U/ml) of IL-1, IL-2, and gamma-IFN production compared with normal mice (2.2 +/- 0.54 U/ml, 16.9 +/- 2.1 U/ml, and 76.0 +/- 3.1 U/ml, P less than 0.01), respectively. However, IL-3 production was significantly less inhibition (46.1%, 2.35 +/- 1.0 U/ml in CsA-P815-treated mice and 4.36 +/- 1.7 U/ml in normal mice) compared with other cytokines (IL-1, IL-2, gamma-IFN). Two systems were employed to assess the immunosuppressive efficacy of antigen-nonspecific Ts cells in vivo. First, adoptive transfer (i.p.) of spleen cells harvested from CsA-P815-treated mice ten days after treatment on 3 consecutive days (days 0, 1, 2) at a 3 x 10(7) cell dose into virgin B6 mice that were immunized with P815 cells (1 x 10(7), day 0) completely inhibited the development of Tc cells against P815 targets (5% specific cytolysis, effector:target ratio [E:T] = 200). The suppressor effect was immunologically nonspecific; adoptive transfer of Ts cells from CsA-P815-treated mice also abrogated the development of Tc cells against third=party BW5147 cells.(ABSTRACT TRUNCATED AT 400 WORDS)     

Effects of parathyroidectomy on renal allograft survival

BACKGROUND: Hyperparathyroidism is a common problem secondary to renal insufficiency and is often not entirely resolved after renal transplantation (TX). METHODS: In this retrospective analysis, the effects of parathyroidectomy (PTX) on allograft function were evaluated and the risk factors involved in allograft deterioration in patients after PTX will be discussed. RESULTS: The rise in creatinine was steeper 1 year after PTX compared to 2 years before PTX in the majority (13 of 22) of patients. Compared to a cohort without PTX, graft survival was significantly decreased by 60% in 6 years (p < 0.0001). After multivariate adjustment, risk factors attributed to graft function included baseline creatinine (p = 0.02), baseline systolic blood pressure (p = 0.04) and time between TX and PTX, but not PTX itself. The peri-PTX drop in serum calcium was significantly more accentuated in patients exhibiting a worsening of graft function after PTX (p = 0.04). CONCLUSIONS: In patients requiring PTX, graft function is in danger of worsening. Since many factors contribute to this negative correlation and no association with parathyroid hormone (PTH) levels before PTX has been observed, we do not recommend prophylactic PTX on the basis of PTH levels only. However, appropriate management of peri-PTX risk factors is highly important. If the clinical situation, e.g. progressive renal osteodystrophy, requires removal of parathyroid glands, the procedure should be performed, if possible, in the presence of stable graft function.     

The effect of two different renal preservation methods on canine renal allograft survival

Summary Preservation of human cadaver kidneys for transplantation has been achieved primarily by two methods, hypothermic pulsatile perfusion with cryoprecipitated plasma and cold storage with an electrolyte solution. It has been suggested that pulsatile perfusion results in an increased antigenicity of the transplanted kidney. To investigate the possibility that pulsatile perfusion causes changes which may accelerate allograft rejection, machine preservation was compared with simple cold storage. The kidneys were preserved by either one of the two methods for 6 or 24 hours followed by allotransplantation in nephrectomised dogs. No immunosuppressive drugs were given.Kidneys which were allografted without undergoing any preservation (0 hrs) had a mean survival time of 10.4±1.7 days (n=5). Kidneys preserved by machine perfusion for 6 and 24 hours survived for 9.6±1.4 (n=5) and 10.9±1.3 (n=9) days respectively. The mean suryival time for simple cold storage for 6 and 24 hours was 9.3±1.3 (n=7) and 12.0±1.9 (n=6) days. Our findings suggest that in kidneys exposed to minimal warm ischaemia there is no significant difference between the two methods of preservation on renal allograft survival for the time intervals tested.     

The timing of pretransplant transfusions and renal allograft survival

Analysis of over 3000 cadaveric renal allograft recipients transplanted between June 1977 and June 1982 as part of the South-Eastern Organ Procurement Foundation Prospective Study was performed to determine the influence of timing of blood transfusions (BT) on patient and graft survival. Four mutually exclusive BT groups were identified for 2480 first-transplant and 655 regrafted patients studied: group 1 (n = 348, 29, respectively) received no BT; group 2 (n = 256, 29, respectively) received perioperative BT only (i.e., at the time of, or within 10 days of transplant); group 3 (n = 972, 287, respectively) received preoperative BT only (i.e., 10 or more days pretransplant); group 4 (n = 904, 310, respectively) received both preoperative and perioperative BT. For first graft recipients, actuarial graft survival for group 2 was significantly greater (P less than 0.035) than group 1 (49% vs. 41% at one year; 35% vs. 25% at 4 years), but to a lesser degree than groups 3 or 4, which were equivalent (58% at one year and 38% at 4 years). For regrafted patients, actuarial graft survival was again significantly greater (P less than 0.03) for group 2 patients, as compared with group 1 (59% vs. 29% at one year), and group 3 and 4 patients were not significantly different from each other (45% and 48% at one year, respectively) or from group 2. Interestingly, for regrafted patients who were presensitized at the time of transplant, those in group 4 (n = 94) had significantly better graft survival than group 3 (n = 111) at all time points examined (54% vs. 47% at one year, 46% vs. 22% at 3 years). In all comparisons, increases in graft survival were associated with decreased graft loss resulting from rejection, and no significant differences in patient survival were seen between any of these groups. These findings indicate that: (1) perioperative transfusions alone may have benefit in decreasing allograft rejection; (2) perioperative transfusions provide no apparent risk for patients who have already received pretransplant transfusions; and, (3) sensitized regrafted patients who receive pretransplant transfusions may gain an additional benefit from perioperative transfusions.     

The effect of body mass index on long-term renal allograft survival

BACKGROUND: A number of factors have been implicated in decreasing long-term renal graft survival. Factors such as living versus cadaveric donor status, acute rejection, and HLA matching have been studied in detail. Mild obesity defined as a body mass index (BMI) of >25 has been found to have a deleterious effect on a number of physiologic processes. We studied the effect of a BMI >25 on long-term renal transplantation outcome. METHODS: A total of 405 patients who underwent transplantation at Saint Barnabas Medical Center from 1990 to 1997 were evaluated. All known variables impacting on long-term graft function were collected. Multivariate analysis utilizing the Cox-proportional hazard model and Kaplan-Meier actuarial survival were applied to these risk factors. RESULTS: BMI >25 was isolated as an independent risk factor for both decreased graft survival and patient survival (relative risk 2.0 for each). Cadaveric donor status, acute rejection, and use of azathioprine versus mycophenolate mofetil were the only other significant risk factors. CONCLUSIONS: Mild obesity before transplantation has a negative impact on long-term renal graft and patient survival.     

The impact of employment status on recipient and renal allograft survival

Abstract: Background:  With the improved median survival of kidney transplant recipients, there has been an increased focus on quality of life after transplantation. Employment is a widely recognized component of quality of life. To date, no study has demonstrated a link between post-transplant employment status and recipient and allograft survival after transplant.
Methods:  The records from the United States Renal Data System (USRDS) and the United Network for Organ Sharing (UNOS) from January 1, 1995, through December 31, 2002, were examined in this retrospective study. Two outcomes, allograft survival time (time between the transplantation and allograft failure or censor) and recipient survival time (time between the transplantation and recipient death or censor), were analyzed using Cox models adjusted for potential confounding factors.
Results:  Compared to patients working full time at the time of transplantation, those not working by choice have a greater risk to graft [hazard ratio (HR) 1.27, p < 0.001] but not to recipient survival. A similar trend was observed in patients not working at 12 months post-transplant (HR 1.30, p < 0.001 for graft survival but not for recipient survival). However, at five-yr post-transplant not working by choice was protective to the graft (HR 0.47, p < 0.01) as compared to working full time. Results of the analysis in the patient subgroups based on the comorbidities and the overall health status were similar.
Conclusion:  Employment status at the time of transplantation and in post-transplant period has a strong and independent association with the graft and recipient survival. Full time employment at the time of transplant and at one-yr post-transplant is associated with lower risk for graft failure and recipient mortality. However, working beyond the time covered by Medicare might be associated with potential risk for graft survival.     

Prolongation of renal allograft survival in DLA tissue-typed beagles after third-party blood transfusions and immunosuppressive treatment.

Significant prolongation of survival of nonrelated DLA-mismatched renal allografts has been obtained in beagle recipients receiving three blood transfusions from nonrelated donors prior to kidney transplantation and immunosuppression after transplantation. Nontransfused DLA-identical or DLA 1 haplotype-different littermates of the transfused dogs were used as controls. Lymphocytotoxic antibodies were formed after the blood transfusions. A quantitative immune reactivity score correlated with graft survival. Low scores prior to transplantation were found in five transfused dogs that did not reject their allografts. High scores prior to transplantation were found in four animals rejecting their graft and in one dog that survived after an abortive rejection episode. The great similarities between the results obtained in this animal model and the observations made in human transplant patients indicate that this model can be utilized for a further analysis of the possibilities of blood transfusions in protecting subsequent renal allografts from immunological rejection.     

Blood transfusions, suppressor T cells, and renal transplant survival

Fifteen men undergoing chronic hemodialysis were transfused with 2 units of packed red cells, none of these patients having been previously transfused. They were studied before and after transfusion to determine suppressor T cell numbers and activity, and to monitor the appearance of cytotoxic antibodies. Although the number of suppressor T cells did not change, their function was significantly increased three weeks after the transfusion. This had largely returned to normal by 20 weeks. No cytotoxic antibodies were produced. Twelve of the patients subsequently received cadaveric renal transplants and nine of these kidneys are currently functioning more than a year after transplantation. Although the blood transfusions may have helped to produce these satisfactory results, it is accepted that the nonspecific increase in suppressor cell function may not have been the only mediator because this activity had returned to normal in most cases by the time the patients were transplanted.