Effect of pretransplant blood transfusions and splenectomy on renal allograft survival in the Lewis rat

Both pretransplant blood transfusions and pretransplant splenectomy have been shown to improve renal allograft survival in humans and experimental animals. A study was undertaken using the Lewis rat to determine if any combination of pretransplant splenectomy and pretransplant blood transfusions exerted either a synergistic or deleterious effect on renal allograft survival. Pretransplant splenectomy and pretransplant blood transfusions used singly significantly prolonged renal allograft survival. Pretransplant splenectomy followed by 3 blood transfusions also significantly prolonged renal allograft survival. This finding implies that secondary sites of suppressor cell activity, for instance lymph nodes, can be stimulated by blood transfusion and produce prolonged allograft survival in the absence of the spleen. No combination of pretransplant blood transfusion and splenectomy was synergistic. In fact, the group that had pretransplant transfusions followed by splenectomy had allograft survival no different from the control group.     

Effect of ultraviolet-B-irradiated donor-specific blood transfusions and peritransplant immunosuppression with cyclosporine on rat cardiac allograft survival

We have previously demonstrated that pretreatment of ACI recipients with ultraviolet-irradiated donor-specific blood transfusion (UV-DST) leads to permanent cardiac allograft survival without further host immunosuppression (ACI rats are weak responders to Lewis lymphocytes in mixed-lymphocyte reaction). This study examines the effect of UV-DST and the timing of transfusions on ACI cardiac allograft survival in Lewis recipients with and without the addition of peritransplant cyclosporine (CsA) (20 mg/kg i.m.) given on days 0, +1, and +2 in relation to the time of transplantation. The mean survival time (MST) of ACI cardiac allografts in Lewis recipients was significantly increased to 33.6 +/- 5.7 days (P less than 0.001) by CsA treatment alone as compared to 6.5 +/- 0.5 days survival in control. When DST was given on day -3 combined with CsA, graft survival was increased to 42.0 +/- 9.3 days (P less than 0.01), as compared to 5.8 +/- 1.3 days when DST alone was used. When DST was irradiated with ultraviolet B (UV-DST) and administered on day -3 combined with peritransplant CsA, the MST was increased to 68.83 +/- 16.1 days as compared to an MST of 10.0 +/- 1.0 days in controls treated with UV-DST alone. When UV-DST was given on day -7 and combined with peritransplant CsA immunosuppression, the results were similar. However, when UV-DST was peritransplant CsA course, 4 of 6 recipients maintained their ACI heart allografts indefinitely (greater than 300 days) in contrast to the effect of UV-DST alone (MST of 13.5 days). Third-party (W/F) UV-irradiated blood transfusions were ineffective in prolonging ACI cardiac allografts in Lewis rats, regardless of whether the transfusions were given alone or in combination with peritransplant immunosuppression with CsA. In conclusion, these results demonstrate that UV-DST combined with a brief peritransplant immunosuppression with CsA induces prolonged heart allograft survival in a histoincompatible, strong responder host, and that such effect is donor specific. The use of UV-DST combined with peritransplant CsA immunosuppression offers a promising approach to achieving organ transplant unresponsiveness, and decreased sensitization to the donor blood elements, which eventually may have important clinical implications.     

Pretransplant blood transfusions with cyclosporine in pediatric renal transplantation

Pretransplant transfusions were repeatedly shown to be associated with improved graft survival in the ”pre-cyclosporine era,” and have recently been shown to be beneficial in patients on modern immunosuppressive regimes. In an attempt to improve this transfusion effect and minimize the potential development of cytotoxic antibodies, we have given these transfusions, with concomitant cyclosporine cover, prior to transplantation. Ninety-two renal transplantations were performed in 91 children in the study group (group 1) and all received pretransplant transfusions with cyclosporine cover. Results were compared with a preceding group of 102 children (104 transplantations) who had received pretransplant transfusions without cyclosporine cover (group 2). There were 70 cadaver and 22 living-related donor (LRD) transplants in group 1, and 88 cadaver and 16 LRD transplants in group 2. Graft survival rates (1- and 5-year) for cadaver transplantation were 96% and 90% in group 1 compared with 78% and 64% in group 2 (P=0.001). For LRD transplantation, these figures were 95% and 87% in group 1 and 81% and 69% in group 2. There was no difference between the two groups in terms of age at transplantation, sex, donor age, HLA-A, -B, -DR mismatches, or cold and warm ischemia times. All cadaver graft recipients received quadruple, sequential immunosuppression post transplant. However, 9 patients in group 1 were changed to tacrolimus for recurrent rejection episodes. No patient developed persistent lymphocytotoxic antibodies post transfusion or side effects of cyclosporine. Cyclosporine can be safely given with whole blood prior to transplantation with no adverse effect and no sensitization. Graft survival was significantly improved in this group of patients and graft loss due to rejection was exceptional. This effect should be further evaluated in prospective studies. Received: 10 June 1999 / Revised: 9 March 2000 / Accepted: 10 March 2000     

Long-term prolongation of cardiac allografts by subtherapeutic levels of cyclosporine in rats conditioned with pretransplant blood transfusions and cyclosporine

This study was aimed at ascertaining whether long-term graft survival was achievable with short term cyclosporine (CsA) therapy or with subtherapeutic doses of CsA in rats conditioned with blood transfusions (BT) combined with CsA. Previous studies had shown that donor-specific transfusions combined with a short course of CsA interacted synergistically, resulting in considerable prolongations of ACI and BUF grafts in LEW hosts receiving no postoperative treatment. The donor-specific depression of alloreactivity was confirmed in the present study by showing a depression of mixed-lymphocyte reaction (MLR) reactivity as well as of humoral antidonor responses in BT-CsA conditioned rats. The effects of postoperative CsA were then studied in recipients conditioned with BT-CsA or BT alone. ACI and BUF cardiac graft survival in LEW hosts conditioned with BT and treated with a five-day postoperative course of CsA (20 mg/kg/day) were indistinguishable from graft survival in untransfused hosts (ACI: 35.6 +/- 15.5 vs. 38.8 +/- 7.4; BUF: 58.4 +/- 39.8 vs. 48.0 +/- 21.7) indicating no interaction between BT and CsA under these conditions. In contrast, the effect of a post-operative five-day course of CsA (10 mg/kg/day) was extended by conditioning the recipients with donor-specific BT and CsA (ACI:41.7 +/- 7.0 vs. 27.4 +/- 11.6; P less than 0.05). More remarkably, a thirty-day course of subtherapeutic doses of CsA (2.5 mg/kg/day) resulted in long-term prolongation (greater than 100 days) of ACI grafts in a large proportion of hosts conditioned with donor-specific BT and CsA, while the majority of controls conditioned with nonspecific BT and CsA or CsA alone rejected their grafts within three weeks (P less than 0.01). The possible mechanisms of this phenomenon are discussed.     

Effect of pretransplant stored donor-specific blood transfusions on early renal allograft survival in one-haplotype living related transplants

The effect of pretransplant stored donor-specific blood transfusions (DSBTs) on early renal allograft survival in 37 consecutive one-haplotype living related donor (LRD) transplants (group B) was compared with a similar consecutive series of 38 one-haplotype LRD recipients (group A) who did not receive DSBTs. All transplant recipients in both groups were treated with identical immunosuppressive protocols using azathioprine and prednisone. Forty patients received pretransplant DSBTs and three of these patients (8%) developed cytotoxic antibodies to their prospective donors. Neither hyperacute rejection nor hepatitis occurred in group B patients following DSBTs. One group B patient experienced a technical graft loss on the 1st postoperative day and was excluded from the rejection data. Graft survival at 3 and 6 months was 100 and 90% in group B recipients and 68% in group A recipients. All 12 group A graft failures resulted from acute nonreversible rejection episodes occurring during the first 3 months post-transplant. The three group B graft failures occurring at 6 months were attributable to chronic vascular rejection. Chronic rejection of the renal allograft was histologically documented in six group A and five group B patients by 6 months post-transplant. The use of stored donor blood offered a simple and easily monitored method of administering pretransplant DSBTs that was convenient to the donor and recipient. The administration of DSBTs did not appear to be harmful to the recipient. In fact, the use of pretransplant stored DSBTs in one-haplotype LRD renal transplantation appeared to improve the prospects of early graft survival in our experience.     

Effect of blood transfusions on renal allograft survival.

One and two-year allograft survival rates of 117 first and 20 second consecutive cadaveric renal allografts are analyzed. The following observations were made: (1) Pretransplant blood transfusions may not improve rate of allograft survival per se. (2) Pretransplant blood transfusions may, however, reduce the number and the severity of rejection episodes in the early posttransplantation period. Thus, the allograft survival, especially in the nontransfused patients, may perhaps be influenced more by the effective manipulation of immunosuppressive therapy during rejection episodes. (3) The presence of lymphocytotoxins per se may not have any deleterious effect on the survival of second allografts.     

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.     

Interrelationship of time of dialysis-dependent uremia and pretransplant blood transfusions.

In a consecutive series of 167 renal allotransplants, a statistically significant correlation was found between the number of pretransplant blood transfusions and the time of dialysis-dependent uremia. This correlation suggests that one possible explanation for the association of a beneficial effect of pretransplant blood transfusions with allograft survival may be in part due to the prolongation of uremia, which is a well-known immunosupressive factor. This begs the question of whether the transfusion-dialysis time association promotes a further selection factor leaving sensitized patients waiting for longer periods of time for transplants or unable to receive transplants at all. Whether the transfusion and the favorable prognosis association is also related to other specific immunological mechanisms remains to be proven.