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PubMed2002

Higher frequency of high-grade rejections in cardiac allograft patients after Quilty B lesions or grade 2/4 rejections.

BACKGROUND: To better understand how different histologic patterns of allograft inflammation found on biopsies of human cardiac allografts progress to high-grade rejection, we undertook a statistical analysis of our institutional database to detect statistical patterns among different types of myocardial allograft inflammations found on sequential biopsies. METHODS: Biopsies were analyzed for statistical associations between high-grade rejections (International Society of Heart and Lung Transplantation [ISHLT] grade > or = 3A/4) and the type of cardiac allograft inflammation found on prior biopsies. Case cross-over and case control designs were used to compare the antecedent patterns of inflammation on biopsies with high-grade rejection compared to biopsies with low-grade rejection, all within the same subject. Quilty lesions were correlated with cyclosporine levels. RESULTS: Patients with Quilty B lesions or ISHLT grade 2/4 rejections show an increased risk for high-grade rejection on their next biopsies (Odds ratio 5.9 to 11.2). The presence of two pathological findings, especially Quilty B and grade 2/4 rejection, creates additional risk in excess of that found independently (Odds ratio >14). Quilty lesions are found only in cardiac allografts, and do not correlate with trough cyclosporine levels. CONCLUSIONS: The morphological patterns of several types of human cardiac allograft inflammation found on sequential protocol biopsies are not randomly associated. Patients with grade 2/4 rejections and Quilty B lesions show an increased risk for high-grade rejections on their next biopsies. Quilty B lesions, similar to ISHLT grade 2/4 rejections, may represent subclinical rejection. Both are more likely to progress to a high-grade rejection.

Biopsy↗

PubMed2006

Reporting of rejection after renal transplantation in large immunosuppressive trials: biopsy-proven, clinical, presumed, or treated rejection?

BACKGROUND: Prevention of acute rejection still is an important endpoint in randomized controlled trials. Poor study reporting may create confusion and render decision-making difficult. The present study thoroughly analyses the presentation and definition of rejection in reports on large multicenter immunosuppressive trials published in the field of renal transplantation. METHODS: Publications of large immunosuppression trials in kidney transplantation were identified by a predefined search strategy. The reported acute and biopsy-proven acute rejection (BPAR) episodes and additional information on number of patients recruited, publication year, impact factor, definition of acute rejection and the reporting of efficacy analyses were extracted. All reports were scanned for (a) at what point and (b) for which signs or reasons a biopsy was performed. RESULTS: Eight of 41 (19.5%) papers investigating rejection rates reported a sufficient definition of acute rejection. Twenty-eight of 41 (68.3%) presented more than one rejection rate and were published in significantly higher impact journals. The absolute difference between clinical rejection and BPAR had a median of 6.5% and a wide range (0-16.9%). Efficacy analysis was presented in all but four (90.2%) reports. Thirteen of 35 (37.1%) papers did report the timing of the biopsies and 25 of 35 (71.4%) publications gave specifications of when a biopsy sample should be taken. CONCLUSIONS: The requirements of proper reporting of rejection episodes are not fulfilled in most of the publications and the use of many different terms for the description of rejection rates is confusing at present. Our comprehensive review clearly demonstrates the need for improved and standardized reporting of rejection episodes and we suggest to report both acute rejection and BPAR.

Biopsy↗

PubMed1997

Mechanisms of allografted tumor rejection: the roles of T cells in allograft rejection mediated by a type of bone marrow-derived macrophage.

Allografted tumor rejection does not occur in the absence of T cells, but the main effector cells responsible for the rejection are allograft-induced macrophages (AIM). We examined the roles of T cells in the AIM-mediated rejection of Meth A (H-2d) tumor cells from C57BL/6 (H-2b) mice. Irradiation of C57BL/6 mice abrogated both the induction of AIM and the allograft rejection. Reconstitution of the irradiated mice with F1 (C57BL/6 X C3H/He: H-2b/k) bone marrow cells led to the appearance of H-2b/k haplotype of AIM exclusively in the rejection site and to allograft rejection, indicating that radiosensitive cells prerequisite for both the induction of AIM and allograft rejection were bone marrow-derived cells, and that the progenitors of AIM existed in the bone marrow cells to be activated into AIM in the rejection site. To understand the role of T cells in the induction of AIM, we used adult-thymectomized, X-irradiated C57BL/6 mice reconstituted with F1 bone marrow (ATXBM). The ATXBM mice could neither induce AIM nor reject allogeneic Meth A cells, whereas adoptive transfer of F1 lymph node T cells to the ATXBM mice restored not only the induction of AIM but also rejection of the allograft. Among the lymph node T cells, CD4-, but not CD8+, cells were found to be essential for the activation of AIM progenitors to AIM; and CD8+ T cells were further required for rejection, at least in part, to enhance the number of AIM in the rejection site.

Adoptive Transfer↗

PubMed1989

Cellular immunity in allograft rejection: role of lymphocyte subpopulations and T-cell subsets in rat cardiac allograft rejection.

In this study, cellular requirements for rejection are examined by the use of adoptive transfer assays in the ACI to Lewis cardiac allograft model. The findings show that adoptive transfer of 1 x 10(8) spleen cells (SpL), 5 x 10(7) T-cells, and 2 x 10(7) helper T-cells (W3/25+) obtained from normal, nonsensitized donors restores acute ACI graft rejection in sublethally irradiated (750 rad) Lewis recipients. In contrast, reconstitution with 2 x 10(7) cytotoxic T-cells (0X8+) does not restore first-set graft rejection. Reconstitution of the irradiated recipients with either W3/25+ or 0X8+ T-cells obtained from specifically sensitized syngeneic donors resulted in acute rejection. The W3/25+ T-cell subset was significantly more potent (P less than 0.01) in effecting rejection on a per-cell basis. Adoptive transfer of SpL, T-cells, and 0X8+ T-cells obtained from sensitized rats led to accelerated cardiac allograft rejection in the naive secondary recipients while W3/25+ T-cells did not. This study suggests that although the W3/25+ T-cells alone have the capacity to initiate first-set graft rejection, both W3/25+ and 0X8+ subsets appear to be critical to the completion of rejection of heart allografts. We also examined the capacity of adoptively transferred B-cells from sensitized donors to influence graft rejection. Our findings suggest that while B-cells fail to restore the capacity for graft rejection in irradiated recipients, they can, however, present MHC antigens to the secondary naive host thus causing allosensitization which results in accelerated rejection of a subsequent graft.

Animals↗

PubMed2006

The cellular basis of cardiac allograft rejection. IX. Ratio of naïve CD4+CD25+ T cells/CD4+CD25- T cells determines rejection or tolerance.

Naïve CD4+ T cells are central to allograft rejection, but include 3-10% CD4+CD25+ T cells that induce and maintain immune tolerance. Whether increasing the ratio of CD4+CD25+ T cells can inhibit rejection and induce tolerance is not known. This study examined the effects that naïve CD4+CD25+ and CD4+CD25- T cells have on rejection of MHC incompatible PVG cardiac allografts in whole body irradiated DA rats. The ratio of CD4+CD25+ T cells to CD4+CD25- T cells was increased to examine if this delayed rejection. CD4+CD25- T cells alone restored near first set rejection time of 8-10 days and were significantly faster than unfractionated CD4+ T cells which nearly always took over 10 days to effect rejection. Enriched CD4+CD25+ T cells, either fresh or cultured with IL-2 and donor alloantigen, did not restore rejection. Admixing naïve CD4+CD25+ T cells with CD4+ T cells at a ratio of 1:10 prevented graft destruction by rejection. Naïve CD4+CD25+ T cells, either fresh or cultured with IL-2 and donor alloantigen, at a ratio of 1:1, prevented significant episodes of rejection and grafts survived >300 days. These grafts had large areas of normal myocardium but had some foci of CD4+, CD8+ and CD25+ cellular infiltration. This study found CD4+CD25- T cells were the principal mediators of rejection and naïve CD4+CD25+ T cells partially inhibited the CD4+CD25- T cells in unfractionated CD4+ T cells. Increasing the ratio of naïve CD4+CD25+ to CD4+CD25- T cells inhibited rejection allowing grafts to survive indefinitely and may induce transplant tolerance, without a need for long-term immunosuppression.

Adoptive Transfer↗

PubMed2000

Increased expression of inflammatory cytokines and adhesion molecules by alveolar macrophages of human lung allograft recipients with acute rejection: decline with resolution of rejection.

BACKGROUND: Alveolar macrophages (AM) are the major population in bronchoalveolar lavage (BAL) cells; we assessed their role in human lung allograft recipients by correlating the expression of adhesion molecules and inflammatory cytokines with clinical outcome of allograft. METHODS: We obtained BAL samples from patients and enriched them for AM in plastic petri dish for 2 hours at 37 degrees C in 5% CO(2). Expression of intercellular adhesion molecule-1 (ICAM-1, CD54), platelet endothelial cell adhesion molecule-1 (PECAM-1, CD31), and CD11c was assessed by flow cytometry using monoclonal antibodies. We assessed cytokine profile using Multi-Probe RNase protection assay. RESULTS: Alveolar macrophages that express CD11c, CD31 and CD54 were increased in patients with either rejection or infection compared with those without rejection and infection. The difference in the percentage of AM expressing CD11c and CD31 between the rejection group and patients without rejection and infection group was statistically significant (CD11c, p < 0.01; CD31, p < 0.03). Interleukin (IL)-1 alpha, IL-1 beta, IL-1 receptor antagonist (IL-1Ra), and IL-6 expression was higher in the rejection group than in patients without rejection. Five out of 9 patients in the rejection group expressed high levels of IL-15 and tumor necrosis factor-alpha compared with patients without rejection and infection. The increased number of AM expressing adhesion molecules and elevated expression of cytokines observed during acute rejection declined to basal levels after successful treatment and resolution of rejection. This study demonstrates that lung allograft rejection is associated with increased expression of adhesion molecules and inflammatory cytokines by AM, which could facilitate mononuclear cell adhesion and extravasation contributing to the allograft injury in lung transplant recipients.

Bronchoalveolar Lavage Fluid↗

PubMed1985

Lung allograft rejection in the rat. III. Corresponding morphological rejection phases in various rat strain combinations.

Rejection of RT1-incompatible lung grafts has been found in the study reported in our accompanying article to result in four consecutive morphological rejection phases: the latent, the vascular, the alveolar, and the destruction phase. The most prominent signs of rejection, however, occur early in the vascular phase in the bronchus-associated lymphoid tissue (BALT) of these grafts. In this study we investigated whether these four phases and the early rejection signs in BALT are universal phenomena of lung allograft rejection. Therefore, various donor-recipient combinations of inbred rat strains, incompatible for the MHC or for minor loci, were compared with respect to histological rejection phenomena--both in the lung graft and in the recipient's spleen--and alloantibody formation. The four rejection phases appeared sequentially in grafts of all combinations. Duration of the phases depended on the degree of histoincompatibility of the graft. Again, BALT was involved early in the rejection process. During the vascular phase a strong immune response developed in the spleen, and in the alveolar phase antibodies circulated in the blood. We conclude that these morphological rejection phases are universal phenomena of the rejection process against lung allografts in rats. Corresponding phenomena have been described for other species, even in immunosuppressed recipients. Based on these data, a new concept of the universal rejection process of lung allografts is postulated.

Animals↗

PubMed1992

Day-5 protocol liver allograft biopsies document early rejection episodes and are predictive of recurrent rejection.

METHODS: The day-5 posttransplant protocol biopsy specimens and clinical courses of 27 consecutive orthotopic liver transplant recipients followed up at least 6 months were reviewed. RESULTS: Twelve (44%) of 27 patients had histologic evidence of rejection on the day-5 biopsy; 8 (67%) of these 12 patients required OKT3 for reversal of the rejection. No significant differences in biochemical liver test results, bile output, or cyclosporine levels were observed between this group and the 15 patients (56%) without histologic evidence of rejection on day 5. Eight (67%) of the 12 patients with rejection had recurrent rejection episodes, with one recurrence each in six patients, two recurrences in one patient, and three recurrences in one patient. Of the 15 patients without rejection on day 5, nine (60%) subsequently had rejection at 10 days, 14 days, and 1 1/2, 3 1/2, 4, 5, and 11 months after transplantation. Only one (11%) of these nine patients had a recurrent rejection episode. There were no differences in the incidence of posttransplant cytomegalovirus infections between the two groups. Two cases of posttransplant lymphoma were seen; they developed in two patients without rejection on the day-5 biopsy. No patients or allografts were lost to acute or chronic rejection. No complications occurred as a result of the day-5 protocol biopsy. CONCLUSION: The day-5 protocol biopsy is useful in detecting rejection episodes that may not otherwise be clinically apparent.

Adult↗

PubMedDate not supplied

Acute pulmonary rejection precedes cardiac rejection following heart-lung transplantation in a primate model.

Twelve Chacma baboons underwent transplantation of the heart and both lungs from donor baboons matched for size and AB blood group. Cyclosporine was given daily orally, by twice daily intravenous injections, or by a single intravenous injection (together with oral azathioprine and, after 2 weeks, methylprednisolone); whole blood trough levels were inadequate in all groups. Survival was from 4 to 29 days, with death resulting from acute rejection of the lungs in 11 and from bronchopneumonia in one. In the 11 animals dying from rejection, histologic examination showed that the heart was spared from severe rejection in all cases but one. In the inadequately immunosuppressed baboon, therefore, acute rejection occurs earlier in the lungs than in the heart. We have now observed what we believe to have been acute pulmonary rejection in the absence of cardiac rejection on five occasions in three patients in our clinical transplantation program. We would suggest that pulmonary rejection must always be strongly suspected if there are any suggestive features, particularly pulmonary shadowing on chest radiographs, despite negative results of tests indicating rejection of the heart. In the absence of any easy method of confirming pulmonary rejection directly (other than open-lung biopsy, which is clearly contraindicated as a routine procedure), we suggest that more attention should be directed toward developing tests for rejection that are not organ specific, rather than relying on techniques that diagnose cardiac rejection only.

Animals↗

PubMed1995

Beyond hyperacute rejection. Accelerated rejection in a discordant xenograft model by adoptive transfer of specific cell subsets.

If hyperacute rejection is prevented in the guineapig (GP)-to-Lewis rat (Lew) cardiac xenograft (CXg) model, an accelerated rejection involving cellular infiltration occurs in 3 to 4 days. In previous work using an adoptive transfer model, we found that this accelerated rejection was facilitated by either sensitized splenocytes or sensitized serum. In the current study, in an attempt to determine which splenocyte subset(s) facilitated this process, sensitized splenocytes, with or without subset depletion were injected, into complement- and natural antibody-depleted Lew recipients of GP CXgs. Graft survival was 4.18 +/- 0.75 days with no injection (n = 11), 4.13 +/- 0.99 days with naive splenocytes (n = 8), 1.80 +/- 0.45 days with sensitized splenocytes (n = 5), 2.67 +/- 1.03 days with CD4(W3/25+) depletion of the sensitized splenocytes (n = 6), 3.13 +/- 0.84 days with CD8(OX8+) cell depletion (n = 8), 4.70 +/- 0.68 days with macrophage depletion (n = 10), and 4.22 +/- 0.41 days with B cell depletion (n = 9). Cellular infiltrates, hemorrhage, myocyte necrosis, and endothelial deposition of IgG, IgM, and fibrin were seen in rejected grafts. In most groups, infiltrating cells consisted of CD4 (W3/25+), CD8 (OX8+), IL2R+ cells, macrophages, and natural killer (NK) cells. However, in the macrophages-depleted group, activated (ED2+) macrophages and NK cells were significantly reduced. Total IgM, anti-GP IgM, and anti-GP IgG rebounded in all groups over several days but were not consistent at the time of rejection. Lewis rats rejecting GP CXgs early had lower final titers than those rejecting later. Total IgG titers rebounded to baseline by posttransplant day 1 and were therefore similar in all groups at the time of rejection. These findings suggest that this accelerated rejection requires interaction between macrophages and B cells, since depletion of either significantly alters the rejection tempo. A possible explanation is that xenoreactive IgG antibodies, synthesized by sensitized B cells, bind their target antigens--but also bind sensitized macrophages through their Fc region, thus causing rejection by antibody-dependent cell-mediated cytotoxicity.

Acute Disease↗

PubMed1996

Impact of first acute rejection episode and severity of rejection on cadaveric renal allograft survival.

A total of 504 renal transplants were performed between 1984 and 1993; 408 (81%) were cadaver grafts. This study evaluated the impact of a first acute rejection episode and the severity of the rejection on cadaveric allograft survival. Acute allograft rejection was based on clinical evaluation and confirmed by renal biopsy. Ten patients were excluded from this study due to early patient or graft loss. Patients were divided into Group I (n = 179), who never experienced acute rejection, and Group II (n = 219), who had an acute rejection episode. Group II patients were divided into IIA (n = 140), who had a mild first acute rejection episode treated with methylprednisolone, and IIB (n = 79), who had moderate or severe acute rejection treated with OKT3. The overall 1-, 2-, 3-, and 5-yr actuarial cadaveric renal allograft survival for Group I was 80%, 76%, 74%, and 68%. The corresponding graft survival for Groups IIA and IIB were 75%, 63%, 58%, and 50%; and 79% 71%, 65%, and 53% [p = 0.03 (I vs IIA), p = NS (I vs. IIB and IIA vs IIB)]. A similar pattern of survival was seen in primary kidney allograft recipients. In conclusion, long-term graft survival was superior in patients who never experienced acute rejection compared to those with rejection. Improvements in long-term graft survival can be accomplished in patients with severe rejection with OKT3 treatment resulting in comparable survival to those with mild rejection.

Actuarial Analysis↗

PubMed2000

Hypercholesterolemia is associated with increased kidney graft loss caused by chronic rejection in male patients with previous acute rejection.

BACKGROUND: Whereas acute rejection is the main risk factor for the occurrence of chronic rejection, mechanisms in addition to the donor-specific immune response probably contribute to late allograft failure. In this study, we investigated the possible role of hypercholesterolemia in the incidence of chronic kidney graft loss. METHODS: By using the actuarial method, we retrospectively analyzed the long-term loss of cadaveric kidney grafts in patients who had a functioning graft at 1 year and had received a transplant and undergone cyclosporin A therapy in our center between 1983 and 1997. RESULTS: As observed previously, patients with acute rejection during the 1st posttransplant year (n=198) had significantly higher actuarial graft loss at 10 years compared with those free of acute rejection (n=244). In patients free of acute rejection at 1 year, hypercholesterolemia (> or =250 mg/dl) had no impact on graft loss at 10 years. On the contrary, in patients with previous acute rejection, those with hypercholesterolemia (n=59) had a higher immunological (36.0% vs. 19.2%; P<0.01) and overall (50.0% vs. 25.3%; P<0.01) graft loss at 10 years compared with patients with serum cholesterol <250 mg/dl (n=139). Among patients with 1st year acute rejection, hypercholesterolemia was associated with a significant increase in graft loss in male but not in female recipients. Multivariate analysis confirmed that hypercholesterolemia was an independent risk factor for chronic graft loss in male patients (P<0.05). CONCLUSION: Hypercholesterolemia is an independent risk factor for kidney graft loss from chronic rejection in male patients with previous acute rejection. Correction of hypercholesterolemia could help to reduce kidney graft loss caused by chronic rejection in this category of patients.

Acute Disease↗

PubMedDate not supplied

Differences in the pathogenesis of first-set allograft rejection and acute xenograft rejection as determined by sequential morphologic analysis.

To examine the pathogenesis of unmodified heart xenograft and allograft rejection, a sequential morphologic analysis was undertaken. Heterotopic cardiac allografts and xenografts were performed by implanting donor hearts into the abdomen of Lewis rats. Xenograft donors were Golden Syrian hamsters and allograft donors were ACI rats. Both xenografts and allografts were excised and examined by light microscopy at specific postoperative intervals. Allograft rejection was found to be a cell-mediated process, beginning with interstitial infiltrates and perivascular cuffing, which progressed to focal myocyte necroses. Ultimately, complete replacement of the myocardium by mononuclear cells was noted in fully rejected hearts. Xenograft rejection was markedly different. Although xenograft rejection was characterized first by interstitial mononuclear cell infiltrates, unlike allografts there was only minimal progression of cellular rejection. Instead, subsequent rejection was characterized by marked interstitial edema and arteriolar vasculitis and thrombosis, leading to extensive infarcts and hemorrhage in fully rejected hearts. Fibrinoid arteriolar changes and the rapid development of edema in the absence of significant cellular infiltrate suggest that cytotoxic antibodies alter xenograft vascular permeability. These data suggest that humoral immunity is largely responsible for acute concordant xenograft rejection, whereas first-set allograft rejection is mainly a cell-mediated process.

Animals↗

PubMed2004

Acute hepatic allograft rejection: a comparison of patients with and without centrilobular alterations during first rejection episode.

The histologic diagnosis of acute hepatic allograft rejection is usually based upon the identification of characteristic portal tract features. In addition to these, centrilobular alterations such as central vein endothelialitis, zone 3 inflammation, and hepatocyte necrosis may also be seen during episodes of acute rejection. The purpose of this study was to identify any differences in the subsequent clinical course of patients with and without centrilobular alterations during their first biopsy-proven episode of acute rejection. Acute rejection was diagnosed at least once in 35 liver recipients who had undergone allograft biopsy. Of these, 15 (43%) had centrilobular alterations in their first posttransplant biopsy. These 15 patients developed ductopenia (60% vs. 30%) and subsequent episodes of acute rejection (53% vs. 25%) more often than did the 20 patients who lacked centrilobular alterations in their first posttransplant biopsy. Time to first episode of acute rejection and rates of subsequent recurrent hepatitis and death were similar between the 2 groups. Patients with centrilobular alterations during a first episode of acute rejection are more likely to have subsequent episodes of acute rejection and to develop features of chronic rejection than are patients without these changes. These patients may benefit from more vigilant clinical follow-up and/or higher levels of immunosuppression.

Acute Disease↗

PubMed1994

Cellular rejection in discordant xenografts when hyperacute rejection is prevented: analysis using adoptive and passive transfer.

Hyperacute rejection of discordant xenografts occurs rapidly, precluding cellular infiltration. Thus the role of cellular rejection in discordant xenografts is debated. Using adoptive transfer of sensitized splenocytes and passive transfer of sensitized serum, we evaluated the influence of cellular and humoral elements on cellular infiltration and rejection in the guinea-pig-to-rat discordant xenograft model. Guinea-pig hearts were transplanted into Lewis rats. Pretransplant, rats underwent splenectomy and plasma exchange and were started on daily cobra venom factor injections. Xenografts rejected faster after adoptive (1, 2, 2 and 2 days) or passive (1, 1, 2 and 2 days) transfer than controls (4, 4, 4 and 4 days; p < 0.05). Macrophages and neutrophils were predominant in early prerejection specimens. Over time, cellular infiltrates were dominated by mononuclear cells. Natural killer cells were present in all groups, as were interleukin 2 receptor positive cells. Our data suggest that either sensitized serum or sensitized cells are capable of initiating an accelerated rejection characterized by cellular infiltration. Despite subtle differences, the population of infiltrating cells was similar in each group. Thus, although rejection may be initiated by either cellular or humoral influences, the ultimate result is the same. We have, therefore, established a small animal model to study cellular rejection in discordant xenografts. This model will help evaluate the role of cell subsets and xenoantibodies in xenograft rejection and will help determine the precise relationship between the two when hyperacute rejection is prevented.

Acute Disease↗

PubMed1998

Contribution of early acute rejection episodes to chronic rejection in a rat kidney retransplantation model.

Chronic graft rejection represents the single most important risk factor for unsatisfactory long-term results after organ transplantation. In addition to various alloantigen dependent and independent factors, acute rejection episodes have been cited as a major immunological risk factor. However, the effects of acute rejection episodes on long-term graft outcome remains unknown. To examine the influence of a single early rejection event on ultimate graft outcome, acutely rejecting rat kidney grafts were retransplanted sequentially into syngeneic rats and their functional and structural behavior assessed over time. LEWxBNF1 kidney allografts and LEW isografts were removed from their LEW recipients after three, four, five and seven days (N = 12/group/time period) and retransplanted into donor strain hosts. The grafts were followed functionally and harvested four, eight, and 32 weeks later. Urinary protein excretion was measured weekly. Kidneys were examined morphologically and immunohistologically using monoclonal antibodies (mAbs) against macrophages (ED-1), T cells and their subsets (CD5, CD4, CD8), MHC class II expression (OX3) and adhesion molecules (ICAM-1 and LFA-1alpha). The mean standard time +/- SD of non-retransplanted allografts was 14.5 +/- two days; isografts functioned indefinitely. At five and seven days, acutely rejecting allografts showed massive cellular infiltrates associated with extensive necrosis. These changes could not be reversed by retransplantation and the syngeneic recipients later died of renal failure. In contrast, most allografts retransplanted earlier in the process recovered completely when retransplanted after three (12 of 12 allografts) and four (7 of 12 allografts) days. During the subsequent follow-up period, urinary protein excretion was comparable in retransplanted allografts and isografts. The increased mononuclear cell infiltration in non-retransplanted allografts seen at three and four days was only occasionally observed during the follow-up period after retransplantation. Only a few sclerosed glomeruli (approximately 15%), mild arterial changes and minimal cellular infiltrates were observed by 32 weeks, which were similar to that seen in retransplanted isografts. A single acute rejection episode was completely reversible and did not progress to chronic rejection if retransplanted into syngeneic donors when the inflammatory changes are still early. Those results demonstrate the critical effect of alloantigen-dependent events on chronic graft deterioration, and indicate that prompt and aggressive treatment of initial acute rejection episodes are beneficial to protect against late deleterious changes in the graft.

Animals↗

PubMed1996

Interstitial rejection, vascular rejection, and diffuse thrombosis of renal allografts. Predisposing factors, histology, immunohistochemistry, and relation to outcome.

Histological and immunohistochemical analyses were made of biopsy specimens from 50 consecutive patients who experienced putative graft rejection. The mean age of the patients was 44.5 years (range, 17-69 years) and 26 were men. There were 67 evaluable allograft specimens, which were grouped according to the histological diagnosis: group 1, acute tubulointerstitial rejection (n = 42); group 2, acute vascular rejection (n = 18); and group 3, diffuse thrombosis (n = 7). Over a follow-up period of 21-57 months, the mean number of rejection episodes was 1.7, 2.8, and 3.3 in groups 1, 2, and 3, respectively. Allograft loss occurred in 7 out of 30, 10 out of 16, and 4 out of 4 patients in groups 1, 2, and 3, respectively. The following histological parameters differed significantly (P < 0.05) among the groups: interstitial edema, congestion of peritubular capillaries, glomerular thrombosis, and glomerular ischemia (group 3 > group 2 > group 1). Interstitial bleeding was seen more often in group 2 and 3 tissues than in group 1 specimens (P < 0.01). Immunohistochemical analyses showed that vascular rejection was associated with WT14 staining for monocytes and macrophages around the tubuli and with interstitial deposition of complement factor 3. With regard to serology, positive anti-endothelial cell antibody-dependent cellular cytotoxicity was associated with vascular rejection and thrombosis of the graft in all patients tested, and with graft loss in 75%. Pre-existent positive anti-IgG immunofluorescence on peritubular capillaries in pretransplant biopsy specimens incubated with patient serum was found in only 3 of the 50 patients, but was associated with graft loss in 2 of the 3. Cytomegalovirus infection was associated with a higher percentage of graft loss. There were significant intergroup differences in panel reactive antibodies before transplantation (P < 0.001), with higher titers in groups 2 and 3. The findings in relation to interstitial rejection are compatible with cellular rejection, while the data on vascular rejection support a humorally mediated pathogenesis.

Adolescent↗

PubMed1996

Late pancreas allograft rejection. Preliminary experience with factors predisposing to rejection.

A case series of 31 cadaveric pancreas transplant recipients who were insulin-independent at least for one year was analyzed for the factors predisposing to late acute rejection (> 12 months posttransplant). Sixty-two pancreas transplants were performed in 61 patients, of whom 53 had functioning allografts 3 months posttransplant; 31 of these had a follow-up > 12 months. Twenty had no evidence of late rejection, whereas 11 had evidence of acute rejection after 12 months. All patients received quadruple induction immunosuppression. No demographic or clinical factors-including donor age, organ cold time, HLA mismatch, age, sex, or race-could distinguish the late acute rejection group. The presence of acute rejection in the first year posttransplant was similar in the late rejectors (21 episodes in 9 of 11 patients) compared with patients without late rejection (31 episodes in 16 of 20 patients). Antilymphocyte induction therapy type had no influence, but the amount of immunosuppression with prednisone and cyclosporine (CsA) at 3 months posttransplant was significantly lower in those patients who experienced late rejection. After the first year posttransplant, CsA 12-hr trough levels were significantly lower in late rejection months (121 +/- 7 ng/ml) compared with each patient's own stable months (183 +/- 5 ng/ml, P < 0.0001). Neither prednisone nor azathioprine dosages differed between teh two groups after the first year posttransplant. Our preliminary results suggest that early under immunosuppression with prednisone and CsA in the first year and 12-hr trough CsA levels less than approximately 180 ng/ml after the first year posttransplant predispose to late pancreatic rejection.

Adult↗