Address for Correspondence: Dr. Hans J. Schlitt Klinik für Abdominal-und Transplantationschirurgie Medizinische Hochschule Hannover D-30623 Hannover, Germany
Supported by the Deutsche Forschungsgemeinschaft, Sonderforschungsbereich 265
In immunologic terms, "rejection" represents the immune response of the recipient against the allograft as well as its consequence, the destruction of the graft. Typical morphologic features of liver graft rejection are an inflammatory infiltration of the portal triads, endothelialitis and bile duct lesions . In transplant aspiration cytology (TAC), a marked immune activation is typical for acute rejection [2, 3]. Clinically, rejection presents with an increase in transaminases (as a sign of parenchymal cell destruction) and/or in bilirubin (parechymal cell dysfunction or bile duct lesions); fever due to systemic cytokine effects may also be present.
These descriptions already suggest that the term "rejection" is not clearly defined. In fact, immunologists, pathologists, and clinicians use the term with a slightly different meaning. The immunologist uses the term to describe for functional description of the immune response occurring after transplantation, whereas the pathologist refers only to the visible inflammatory response and its consequences inside the graft. The clinician, in contrast, generally refers to rejection as graft damage or dysfunction caused by the alloimmune response. Particularly under the conditions of immunosuppression, however, the alloimmune response per se as well as its morphologic correlates are not necessarily associated with clinical or biochemical signs of graft destruction. This differences in perception of "rejection" are an important cause for misunderstandings between clinicians, pathologists and immunologists.
Transplant aspiration cytology (TAC) has proven to be a particularly useful method for routine monitoring of intragraft immune events after liver transplantation . It is well tolerated by the patients and can be frequently performed irrespective of thrombocyte counts and coagulation parameters. Detailed studies using TAC for routine monitoring have shown that intragraft immune activation is a very sensitive marker for acute rejection. However, rejection-like immune activation can also be observed frequently in clinically asymptomatic patients, particularly in the first four weeks after liver transplantation . Thus, the specificity and the positive predictive value of intragraft immune activation for clinically manifest rejection is rather low. Follow-up of those patients actually showed spontaneous disappearance of immune activation within several days even without a change in immunosuppressive treatment. Similar episodes of rejection-like inflammation in the graft could also be detected by routinely performed core biopsies and histologic evaluation [4, 5]. This suggests that morphologic patterns of rejection - in the absence of severe parenchymal damage in histology - may occur without clinical signs of graft dysfunction. Overall, morphology has proven to be very sensitive for detecting rejection, but its reliability for the diagnosis of clinically relevant rejection is clearly limited.
The term "subclinical rejection" has been applied to describe episodes with morphologic signs of rejection in the absence of clinical rejection. These episodes are observed mainly in the early course after transplantation when (clinical) acute rejection would also be most likely to occur. The incidence of subclinical rejection and its relation to clinical rejection episodes varies with the immunosuppressive treatment used . This suggests that not only the quantity, but also the quality of the alloimmune response can modified by the type of immunosuppressive regimen applied. Animal model have also shown that the degree of histocompatibility may influence the relation between subclinical and clinical rejection. In certain strain combinations and under defined treatment regimens, morphologic evidence of rejection without functional consequences can be present in liver grafts within the first two weeks after transplantation [6, 7].
Most likely, subclinical rejection represents a type of alloresponse that is qualitatively different from the alloresponse leading to clinical graft rejection. So far, the differences in the infiltrates associated with clinical and with subclinical rejection are not completely understood. Cytotoxic cells against the alloantigens of the graft can be cultured from both types of infiltrate [7, 8]. However, some differences in cytokine production profiles between the two types of infiltrate with less IL-4 production and a lower expression of the IL-2 receptor in subclinical rejection have been suggested . A Th1/Th2 shift as explanation for the difference has been discussed but still remains speculative . Recently, a role for immunocompetent passenger cells in subclinical rejection has also been proposed . Whatever the underlying mechanisms are, subclinical rejection has no obvious negative consequences in clinical liver transplantation. In contrast, it seems to be associated with a markedly lower rate of chronic rejection in the long-term course .
These observations show that morphologic rejection without clinical symptoms is not an uncommon finding after liver transplantation. It seems to represent a spontaneously reversible type of alloimmune response without destructive potential ("subclinical rejection"). Treatment is only required if clinical or biochemical signs of graft dysfunction indicate an aggressive component of the ongoing immune reaction ("clinical rejection"). This suggests that routine monitoring of liver allografts by protocol biopsies is not generally necessary for clinical practice, although it is useful for studying immune processes in the graft and for evaluating immunological effects of new immunosuppressive treatment protocols.
It has to be kept in mind, however, that unusual and yet clinically relevant types of alloresponse can occur in individual cases. Recently, a liver transplanted patient presented with malaise and high fever about one week after transplantation. There was no evidence of infection. A liver biopsy showed evidence for rejection, but there were no biochemical signs of graft dysfunction or damage. Fever and the graft infiltrate finally disappeared after high dose steroid and OKT3 treatment. This course suggests that the illness of the patient was due to systemic, probably cytokine-mediated, effects of an intensive alloimmune response without destructive potential.
According to basic immunologic principles an immune reaction toward the alloantigens will generally occur after allogeneic organ transplantation unless the recipient is completely immunoincompetent [Figure 1]. The type and extent of the immune response, however, can be highly variable. It is influenced by many factors, particularly the immunosuppressive treatment and the degree of tissue mismatch between donor and recipient. Due to a functional heterogeneity of the alloresponse, a discrepancy between morphological and clinical aspects of the immune response may result, particularly under the modulatory effects of immunosuppression. The immunologic interaction between the recipient's immune system and the graft does not necessarily lead to destruction of the graft but may have beneficial effects. In fact, an active immune process is also required for the induction of graft acceptance or tolerance . Under these aspects it might be beneficial to select immunosuppressive treatments after liver transplantation by aiming at a low rate of clinical, but a high rate of subclinical rejection.
Lautenschlager I, Höckerstedt K, Ahonen J, et al: Transplantation 46:47, 1988.
Schlitt HJ, Nashan B, Wittekind C, et al: Transplantation 51:786, 1991.
Schlitt HJ, Nashan B, Krick P, et al: Transplantation 54:263, 1992.
Williams JW, Foster PF, Sankary HN: Semin Liver Dis 12:60, 1992.
Ruiz P, Coffmann TM, Howell DN, et al: Transplantation 45:1, 1988.
Farges O, Morris P, Dallman MJ: Hepatology 21:767, 1995.
Dallman MJ, Wood KJ, Morris PJ: J Exp Med 165:566, 1987.
Dallman MJ, Shiho O, Page TH, et al: J Exp Med 173:79, 1991.
Lowry RP: Transplant Sci 3:190, 1993.
Schlitt HJ, Kanehiro H, Raddatz G, et al. Transplantation 56:1001, 1993.
Farges O, Nocci Kalil A, Sebagh M, et al: Transplant Proc 27:1142, 1995.
Lafferty KJ: Clin Transplant 8:181, 1994.
Variability of the immune response against an allograft. The immunological situation of every transplanted patient is located somewhere in between the two extremes. A certain extent of alloreactivity - and thereby of rejection in its strict immunological sense - is always present. Moreover, the quality of the immune response is not uniform and therefore the clinical relevance of the immune response may also be variable.