Kinetics of Intragraft Cytokine Expression, Cellular Infiltration, and Cell Death in Rejection of Renal Allografts Compared With Acceptance of Liver Allografts in a Rat Model

Sharland, Alexandra; Shastry, Suma; Wang, Chuanmin; Rokahr, K. L.; Sun, Junhong; Sheil, A. G. R.; McCaughan, Geoffrey W.; Bishop, G. Alex

doi:10.1097/00007890-199805270-00015

Cited by 73 publications

(45 citation statements)

References 57 publications

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“…This shows that an active immune response is taking place in the graft and probably precedes the development of tolerance, a phenomenon that has already been documented in certain transplant models [2, 101. The question arises as to the nature of that "protective" infiltrate and the operating non has been particularly well documented in certain liver transplant models in rodents [16]. In those models, tolerance is accompanied by an intragraft Thl cytokines upregulation [2, 161.…”

Section: Fig 2 Normalized Transcription Levels Of T Cell-derived Intmentioning

confidence: 99%

Paradoxical early upregulation of intragraft Th1 cytokines is associated with graft acceptance following donor-specific blood transfusion

et al. 2003

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Donor-specific blood transcfusion (DSBT) promotes graft acceptance in certain experimental and clinical situations. However, the exact nature of the operating mechanisms, and in particular the role of Thl/Th2 cytokines, remains controversial. We recently described a fully mismatched rat combination [RA rat (RTlp) to PVG rat (RTlc)] in which a single pre-transplant (Tx) DSBT induces donor-specific tolerance following heart transplantation (Htx). In order to delineate better the role of Thl and Th2 cytokines in the development of tolerance versus rejection, we studied the intragraft mRNA for Thl and Th2 cytokines at different time points post-Tx in rejecting and DSBT-tolerized heart grafts. We performed reverse transcriptase-polymerase chain reaction (RT-PCR) to examine intragraft Thl/Th2 cytokines profile. In contrast to findings from previous data, we detected an early (post-Tx day 2) Thl cytokine upregulation. Thl downregulation/Th2 immune deviation was observed only at a later period (post-Tx day 30). Consistent with this Thl early upregulation, a dense mononuclear cellular infiltrate was seen in tolerized grafts, which was equivalent to that seen in rejecting grafts. Despite in vivo unresponsiveness, peripheral lymphocyte derived from tolerant animals proliferated against donor-matched antigens to the same degree as against those of a third party until post-Tx day 30. Altogether, these observations (dense graft cellular infiltrate, early post-Tx Thl cytokine production, early preserved cellular proliferative responses), suggest that the development of tolerance is preceded by an active Thl cytokine-mediated immune response. The mechanisms by which an early Thl response promotes tolerance need to be further studied.Keywords Cytokine . Tolerance Donor-specific blood transfusion established immunomodulatory strategy to promote graft acceptance, clinically and experimentally [3, 151. Introduction Tolerance can be induced by various immunomodula-However, -the nature of the operaiing mechanisms, in tory strategies. In certain models, induction of toler-particular the role of the Thl/Th2 cytokines balance, ance is accompanied by a Thl downregulation/Th2 remains controversial. We recently developed a rat immune deviation, but data have been conflicting [20]. model in which a single pre-transplant (Tx) DSBT inDonor-specific blood transfusion (DSBT) is a well-duces donor-specific tolerance after heart transplanta-

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Section: Fig 2 Normalized Transcription Levels Of T Cell-derived Intmentioning

confidence: 99%

Paradoxical early upregulation of intragraft Th1 cytokines is associated with graft acceptance following donor-specific blood transfusion

et al. 2003

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“…63 Subsequently, in liver or heart transplants in the process of being accepted, many apoptotic cells were observed in areas of leukocyte infiltrate. 64,65 Apoptosis was not confined to grafts of liver-tolerant recipients, but also occurred in recipient lymphoid tissues. 59,66 Detailed analysis of the liver-infiltrating cells by flow cytometry analysis showed that many of the infiltrating leukocytes were apoptotic, whereas few apoptotic cells could be detected in the infiltrate of rejecting kidney allografts in the same strain combination.…”

Section: Leukocyte Apoptosis Is Associated With Spontaneous Tolerancementioning

confidence: 99%

“…59 The pattern of infiltration of tolerant compared with rejecting grafts supported these findings, with an early rapid increase in T cells and IL-2 receptor-expressing cells in tolerant liver grafts that peaked on day 3. 65 This was accompanied by extensive apoptosis of activated T cells in the infiltrate and recipient lymphoid tissues, 59 followed by a decline in activated cells in the tolerant liver grafts by day 5 and thereafter. 65 Conversely, there was an inexorable increase in the numbers of T cells and activated cells in the rejecting grafts that was slower than in the tolerant livers, but eventually culminated in much greater levels of activation and irreversible rejection.…”

Section: Leukocyte Apoptosis Is Associated With Spontaneous Tolerancementioning

confidence: 99%

“…65 This was accompanied by extensive apoptosis of activated T cells in the infiltrate and recipient lymphoid tissues, 59 followed by a decline in activated cells in the tolerant liver grafts by day 5 and thereafter. 65 Conversely, there was an inexorable increase in the numbers of T cells and activated cells in the rejecting grafts that was slower than in the tolerant livers, but eventually culminated in much greater levels of activation and irreversible rejection. 65 Additional evidence for the association between apoptosis of infiltrating cells and liver allograft tolerance was the observation that treatments that led to liver rejection resulted in a corresponding decrease in apoptosis within the liver.…”

Section: Leukocyte Apoptosis Is Associated With Spontaneous Tolerancementioning

confidence: 99%

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Immune activation is required for the induction of liver allograft tolerance: Implications for immunosuppressive therapy

Bishop

McCaughan

2001

Liver Transpl

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Liver transplants in many animal models are unusual because often they are not rejected even when transplanted across complete major histocompatibility complex barriers without immunosuppression. Their paradoxical behavior is even more obvious when the immune mechanism of acceptance is examined. Instead of acceptance resulting from a lack of immune response to the graft, the opposite occurs, and there is an unusual extensive increase in immune activation in acceptance compared with rejection. This abnormal extensive immune activation is driven by

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“…1,10,11 Research needs to be directed to detect these early events in humans using either peripheralblood lymphocytes or lymphocytes from within the allograft, perhaps using fine-needle aspiration. Such studies may need to be performed in the first week posttransplantation and may potentially identify at the immune response level patients who require less and, eventually, no immunosuppression.…”

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confidence: 99%

Withdrawal of immunosuppression in liver transplant recipients: Is this as good as it gets?

McCaughan

2002

Liver Transplantation

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CommentsThere is a long-held belief that liver allografts are more tolerogenic than other vascularized organs, and as such, it has been predicted that some human liver transplant recipients may survive long term without immunosuppressive drugs. This belief is founded on the following evidence 1-5 : (1) liver transplants may be spontaneously accepted in outbred animal strains; particularly pigs and rodents; (2) single episodes of allograft rejection in humans do not adversely affect allograft outcomes; (3) chronic liver allograft rejection is uncommon (Ͻ5%); and (4) reports of isolated cases of withdrawal of immunosuppression with favorable long-term outcomes. These cases have arisen in the setting of noncompliance or intolerable side effects of immunosuppression, in particular, lymphoproliferative disorders.However, it should be noted that liver allograft rejection occurs at relatively the same frequency as in other allografts (30% to 50%).These data consequently led to programs of immunosuppressive withdrawal in human liver allograft recipients. [6][7][8] Early reports identified small numbers of patients in whom successful withdrawal took place. Such patients usually were more than 5 years posttransplantation and had not experienced recent or significant episodes of rejection (Table 1). Patients considered for withdrawal in these studies usually had considerable side effects from therapy. Successful withdrawal was seen in 20% to 30% of patients, although 20% to 30% developed allograft rejection on withdrawal of therapy.What about this recent report? 9 Does it significantly advance the concept and/or feasibility of withdrawal of immunosuppression?On the surface, this report is encouraging. Unlike previous studies, a significant number of patients were part of a proactive program of immunosuppression withdrawal in the sense that patients were electively weaned, rather than weaned because of drug side effects. The study also was conducted in children and recipients of live donor allografts; both situations theoretically might increase success. Sixty-three patients were selected for drug withdrawal (only 26 patients, elective); withdrawal was slow, taking 3 to 6 months; and overall success was obtained in 24 of 63 patients (38.1%).Well, what is the problem? The problem is in the detail, particularly the denominator. We all would like some estimate of the percentage of patients in our clinics who can be withdrawn electively from therapy. This information is not available from earlier studies. It is available in this report, but not presented in the abstract. The group performed transplantation on 407 patients between 1990 and October 1999. They studied 255 patients who were 408Liver Transplantation, Vol 8, No 4 (April), 2002: pp 408-410 Abstract Unavailable.Please See Print Journal.

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Kinetics of Intragraft Cytokine Expression, Cellular Infiltration, and Cell Death in Rejection of Renal Allografts Compared With Acceptance of Liver Allografts in a Rat Model

Cited by 73 publications

References 57 publications

Paradoxical early upregulation of intragraft Th1 cytokines is associated with graft acceptance following donor-specific blood transfusion

Paradoxical early upregulation of intragraft Th1 cytokines is associated with graft acceptance following donor-specific blood transfusion

Immune activation is required for the induction of liver allograft tolerance: Implications for immunosuppressive therapy

Withdrawal of immunosuppression in liver transplant recipients: Is this as good as it gets?

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