mrm~d cs Plmvlowlrer Q Elsevier, Paris
( 1993 46, 53-55
53
Guest
editorial
Current problems in organ transplantation B Charpentier
Summary
- Organ transpiant~ti~~ has evolved over the past 30 years, although ‘new‘ and ‘old’ problems remain *.msolvsd, which from a personal point of view, might be summarized as: i) the transfusion effect; ii) KLA matching and pre-graft sensitization of the potential recipient: iii) immunosuppressive drugs: iv) the pathogenesis of chronic rejection: v) infections: vi) (k* 1io\‘i) cancers. The aim is ;o attain a state of specific immunological tolerance without the use of immunosuppressive drugs. allograft I rejection I tolerance I immunosuppressant
of time has elapsed
Although organ transplantation has been utilized for more than 30 years as treatment for major organ failure, a growing number of puzzling questions still remain unsolved. This is due to the rela‘live ignorance regarding the basic mechanisms of organ rejection, transplantation tolerance and precise molecular effects of immunosuppressive drugs. It is my belief that at least 6 problems should be considered together with one major hope for the future: the induction of specific transplantation tolerance. This goal can be attained by utilizing severa! a~pr~ches: tolerated xenogeneic transpIantation using gene transfected animals, immune competition by synthetic peptides, induction of clonal anergy and specific immune suppression.
although nobody has hem able to exactly determine the mechanisms of the immunological effect of transfusion. Provocative data which have become recently available tend to demonstrate that no transfusion effect can be evidenced on allograft survival in the early 1990’s during the cyclosporine era. Moreover, the recent problems encountered with viral transmission (Hbs, Hvv C, HIV and others), were counterbalanced by the notion of there being less beneficial results in ‘naive’ patients or to the fact that the risk of viral contamination is greater with the graft itself. It may be time for a better assessment of the transfusion effect with a small number of blood units (I...). trying for example to confirm the data of the Dutch group where transplantation tolerance is reached provided that there are common 1 HLA DR and I HLA B loci between the blood donor and the recipient.
Since the discovery of Terasaki in 1974, which was tailed “beneficial transfusion effect on in-
It is a demonstrated
duced immunological
cipients
tolerance”,
a certain
amount
fact that well-matched improve graft survival in kidney. and
realso
54
in pancreas and heart transplantation. But there is also debate regarding th< benefits cf matching when considering the current rs the historical use of sera and also the burden of work secondary to shipping organs from one continent to another. It is clear that the effect of matching is better seen with time, and is worthwhile For immunized patients. Such patients have had blood transfugraft sions, pregnancies, or have experienced failure. Few means are available to remove these anti-HLA antibodies, and immunoabsorbtion to remove antibodies in highly sensitized patients does not achieve a 100% success rate, although the published results justify continued investigation. It is hoped that the use of rEpo together with better graft survival will ensure that less sensitized patients are placed on the waiting list.
Chronic rejection nrrd growth factors It has become clear that a significant proportion of grafts fail within several years after placement, primarily because of progressive and irreversible immunological attack, in the poorly defined condition of ‘chronic allograft rejection’. For example, less than SO% continue to function at 6 years whereas 80% are satisfactory at one year; and the incidence of coronary arteriosclerosis in heart grafts reaches 50% before 5 years, leading to a 25% mortality rate. Thus, although strong doses of immunosuppressants are given, chronic rejection is an inexorable and poorly understood process, which is as yet uncontrollable. The common denominator of the process is an obliterative fibrosis of hollow structures within the grafts (vessels, interstitium, bronchioles, bile ducts), with the major aspect of obliterative endarteritis secondary to proliferation of endothelium and myofibroblasts, Mediators in chronic rejection include most of the well-known growth factors such as PDGF, EGG, FGF, TGF and also most of the derivatives of arachidonic acid. Cytokines such as ILl, TNF, IFN gamma, anti-HLA antibodies and non-MHC antigens have been suspected. On the other Fend, MHC class II molecules, specialized cells beariui: class II MHC molecules such as dendritic cells, and adhesion molecules (LFAl, ICAM 1) may be of paramount importance. Further studies are needed for a better understanding and treatment of this condition.
Imperfection of immunosuppression Following the intrcjduction of cyclosporine in the early 198Os, numerous drugs became known. KF.506 is impressive in the treatment in liver transplantation, where it is used for the treatment of failing -liver due to acute or chronic rejection in patients with CyA. However, the result of its use in kidney and heart must be confirmed by multicentric data! a& the other hand, side-effects such as nephrotoxicity and neurotoxicity need to be better ascertained. Other immunosuppressive agents have been developed, such as rapamycin, RS61443 (a mycophenolic acid ester) which need further evaluation as immunosuppressants. The use of monoclonal and polyclonal antibodies always raises the problem of how best to use them (prophylactic vs therapeutic vs sequential). The use of other monoclonal antibodies is of great interest, especially the use of antibodies against IL-2R. Many anti p.55 IL2R antibodies have been developed, and most of them showing a strong prophylactic effect on allograft rejection, have good tolerance and mostly fewer side-effects such as infection in treated patients. The effect of an anti-CD7 monoclonal antibody has been disappointing and the effects of anti-ICAMl and anti-LFAl monoclonal antibodies have not yet been determined.
A large number of reports deal with the treatment of patients receiving various organ transplants, and the prevention and treatment of CMV infections. Ganciclovir appears, to constitute an advance in treatment of patients with invasive CMV disease, and along with prevention (using either acyclovir and hyperimmune globulin or hyperimmune globulin alone) provided protection against infections in the sero-negative recipient of an organ from a seropositive donor. Obviously, it would be preferable and less expensive to avoid transplanting a seropositive organ into a negative recipient where possible. Cancer Cancer and lymphoproliferative disorders usually occur after transplantation and tend to confirm the fear that this becomes an increasing probiem as the potency of immunosuppression increases. Tumour registry confirms that virtually all
55
cancers with the exception of breast aud prostate showed an increased incidence in the transplant population, and that the risk of developing a tumour was particularly high for skin cancers, non-Hodgkins lymphomas, Kaposi’s sarcoma and uterine cervical cancer. Some data provided the ominous statistic of 66% incidence of some form of cancer in the transplant population at 20 years after renal transplantation.
transpla~tat~~l~. No one can predict how long it will take before allogeneic recognition and allogeneic (and xenogeneic) tolerance can be fully understood and applied to human transplantation, But in view of the large amount of scientific publications and the quality of the scientific teams involved in this field, major advances are expected in the near future.
Conclusion
Ackmowledgments
The problems listed above are not exhaustive. They constitute only a small proportion of the tangle that must be unravelled in the context of organ
This work was supported hy grants from INSERMICNAMTS, ARC, DRC APAiP. The skiiful assistance of Mrs Levillain is greatly appreciated.
( 1993 46, 53-55
53
Guest
editorial
Current problems in organ transplantation B Charpentier
Summary
- Organ transpiant~ti~~ has evolved over the past 30 years, although ‘new‘ and ‘old’ problems remain *.msolvsd, which from a personal point of view, might be summarized as: i) the transfusion effect; ii) KLA matching and pre-graft sensitization of the potential recipient: iii) immunosuppressive drugs: iv) the pathogenesis of chronic rejection: v) infections: vi) (k* 1io\‘i) cancers. The aim is ;o attain a state of specific immunological tolerance without the use of immunosuppressive drugs. allograft I rejection I tolerance I immunosuppressant
of time has elapsed
Although organ transplantation has been utilized for more than 30 years as treatment for major organ failure, a growing number of puzzling questions still remain unsolved. This is due to the rela‘live ignorance regarding the basic mechanisms of organ rejection, transplantation tolerance and precise molecular effects of immunosuppressive drugs. It is my belief that at least 6 problems should be considered together with one major hope for the future: the induction of specific transplantation tolerance. This goal can be attained by utilizing severa! a~pr~ches: tolerated xenogeneic transpIantation using gene transfected animals, immune competition by synthetic peptides, induction of clonal anergy and specific immune suppression.
although nobody has hem able to exactly determine the mechanisms of the immunological effect of transfusion. Provocative data which have become recently available tend to demonstrate that no transfusion effect can be evidenced on allograft survival in the early 1990’s during the cyclosporine era. Moreover, the recent problems encountered with viral transmission (Hbs, Hvv C, HIV and others), were counterbalanced by the notion of there being less beneficial results in ‘naive’ patients or to the fact that the risk of viral contamination is greater with the graft itself. It may be time for a better assessment of the transfusion effect with a small number of blood units (I...). trying for example to confirm the data of the Dutch group where transplantation tolerance is reached provided that there are common 1 HLA DR and I HLA B loci between the blood donor and the recipient.
Since the discovery of Terasaki in 1974, which was tailed “beneficial transfusion effect on in-
It is a demonstrated
duced immunological
cipients
tolerance”,
a certain
amount
fact that well-matched improve graft survival in kidney. and
realso
54
in pancreas and heart transplantation. But there is also debate regarding th< benefits cf matching when considering the current rs the historical use of sera and also the burden of work secondary to shipping organs from one continent to another. It is clear that the effect of matching is better seen with time, and is worthwhile For immunized patients. Such patients have had blood transfugraft sions, pregnancies, or have experienced failure. Few means are available to remove these anti-HLA antibodies, and immunoabsorbtion to remove antibodies in highly sensitized patients does not achieve a 100% success rate, although the published results justify continued investigation. It is hoped that the use of rEpo together with better graft survival will ensure that less sensitized patients are placed on the waiting list.
Chronic rejection nrrd growth factors It has become clear that a significant proportion of grafts fail within several years after placement, primarily because of progressive and irreversible immunological attack, in the poorly defined condition of ‘chronic allograft rejection’. For example, less than SO% continue to function at 6 years whereas 80% are satisfactory at one year; and the incidence of coronary arteriosclerosis in heart grafts reaches 50% before 5 years, leading to a 25% mortality rate. Thus, although strong doses of immunosuppressants are given, chronic rejection is an inexorable and poorly understood process, which is as yet uncontrollable. The common denominator of the process is an obliterative fibrosis of hollow structures within the grafts (vessels, interstitium, bronchioles, bile ducts), with the major aspect of obliterative endarteritis secondary to proliferation of endothelium and myofibroblasts, Mediators in chronic rejection include most of the well-known growth factors such as PDGF, EGG, FGF, TGF and also most of the derivatives of arachidonic acid. Cytokines such as ILl, TNF, IFN gamma, anti-HLA antibodies and non-MHC antigens have been suspected. On the other Fend, MHC class II molecules, specialized cells beariui: class II MHC molecules such as dendritic cells, and adhesion molecules (LFAl, ICAM 1) may be of paramount importance. Further studies are needed for a better understanding and treatment of this condition.
Imperfection of immunosuppression Following the intrcjduction of cyclosporine in the early 198Os, numerous drugs became known. KF.506 is impressive in the treatment in liver transplantation, where it is used for the treatment of failing -liver due to acute or chronic rejection in patients with CyA. However, the result of its use in kidney and heart must be confirmed by multicentric data! a& the other hand, side-effects such as nephrotoxicity and neurotoxicity need to be better ascertained. Other immunosuppressive agents have been developed, such as rapamycin, RS61443 (a mycophenolic acid ester) which need further evaluation as immunosuppressants. The use of monoclonal and polyclonal antibodies always raises the problem of how best to use them (prophylactic vs therapeutic vs sequential). The use of other monoclonal antibodies is of great interest, especially the use of antibodies against IL-2R. Many anti p.55 IL2R antibodies have been developed, and most of them showing a strong prophylactic effect on allograft rejection, have good tolerance and mostly fewer side-effects such as infection in treated patients. The effect of an anti-CD7 monoclonal antibody has been disappointing and the effects of anti-ICAMl and anti-LFAl monoclonal antibodies have not yet been determined.
A large number of reports deal with the treatment of patients receiving various organ transplants, and the prevention and treatment of CMV infections. Ganciclovir appears, to constitute an advance in treatment of patients with invasive CMV disease, and along with prevention (using either acyclovir and hyperimmune globulin or hyperimmune globulin alone) provided protection against infections in the sero-negative recipient of an organ from a seropositive donor. Obviously, it would be preferable and less expensive to avoid transplanting a seropositive organ into a negative recipient where possible. Cancer Cancer and lymphoproliferative disorders usually occur after transplantation and tend to confirm the fear that this becomes an increasing probiem as the potency of immunosuppression increases. Tumour registry confirms that virtually all
55
cancers with the exception of breast aud prostate showed an increased incidence in the transplant population, and that the risk of developing a tumour was particularly high for skin cancers, non-Hodgkins lymphomas, Kaposi’s sarcoma and uterine cervical cancer. Some data provided the ominous statistic of 66% incidence of some form of cancer in the transplant population at 20 years after renal transplantation.
transpla~tat~~l~. No one can predict how long it will take before allogeneic recognition and allogeneic (and xenogeneic) tolerance can be fully understood and applied to human transplantation, But in view of the large amount of scientific publications and the quality of the scientific teams involved in this field, major advances are expected in the near future.
Conclusion
Ackmowledgments
The problems listed above are not exhaustive. They constitute only a small proportion of the tangle that must be unravelled in the context of organ
This work was supported hy grants from INSERMICNAMTS, ARC, DRC APAiP. The skiiful assistance of Mrs Levillain is greatly appreciated.
