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Transplantation
Transplantation Editorial overview Terry B Strom and Herman Waldmann Beth Israel Hospital,
Boston,
Massachusetts, USA and Sir William Oxford, UK
Current
Opinion
in Immunology
Refinements in immunosuppressive protocols and means to prevent and treat infectious diseases have led to a gratifiring improvement in successful short-term engraftment of allogeneic tissue and patient survival [l]. Nonetheless, unsolved problems abound in the field of transplantation. Although our immunosuppressive protocols have improved, they are still not able to universally prevent rejection and certainly do not uniformly create a state of graft tolerance. Indeed, the basic mechanisms underlying rejection (Nickerson et al., pp 757-764) or graft versus host disease (Waldmann et al., pp 777-783), and creation of the tolerance state have not been firmly established. Although our newer immunosuppressive protocols aIe vastly improved in their capacity to prevent or extinguish acute rejection (Sharma et al., pp 784-790, and Krensky and Clayberger, pp 791-796), we have made no headway in dampening the tempo of chronic rejection (Azuma and Tilney, pp 770-776).
1994,
Dunn School of Pathology,
6:755-756
stimulation in vitro, blockade of only the B7 to CD28 interaction produces anergy. For several years it has been known that B7 expressed on APCs can bind to either CD28 or CTLA4 T-cell surface proteins. More recent data, reviewed by Boussiotis et al., emphasize that at least two and probably three different B7 proteins exist. The expression of B7 proteins on various resting or stimulated cells may vary. Moreover, the signals imparted by individual B7 proteins may lead to very different outcomes on the nature of T-cell activation. It has also become clear that activation of CD28, a low-affinity site for B7-1, but not CTLA-4, a high-affinity site, leads to effective co-stimulation. There is potential for creating tolerance to alloantigens or autoantigens in the clinic through blockade of the CD28 pathway co-stimulation. As noted by Azuma and Tilney, improvements in immunosuppressive protocols and other aspects of clinical management have resulted in an enhanced rate of 1 year graft survival for kidney, pancreas, heart and liver transplants. Despite these improvements, the fate of grafts that are functioning well 1 year aftei&3nsplantation is precisely the same-as noted several decades ago. In short, the outlook for overcoming or preventing acute rejection has improved greatly while we have made no headway in preventing or treating chronic rejection.
Nickerson et al. review the data showing that antigenactivated CD4+ T cells can be subclassed on the basis of patterns of cytokine secretion. Many studies have indicated that the nature of the immune response to an antigen is strongly influenced by the profile of cytokines expressed by antigen-activated CD4+ T cells. Rejection is associated with vigorous expression of IL-2 and IFNy. In contrast, IL-2 and IFNy expression are markedly depressed in tolerized hosts, whereas expression of IL-4 is unimpaired or even enhanced. Is rejection necessarily mediated by the T helper (Th) 1 cells? Is tolerance caused by ‘unopposed’ Th2 cell activity?
Azuma and Tilney’s review emphasizes that both antigen-dependent and antigen-independent events can cause chronic rejection. The same type of pathologic changes are seen in both circumstances. Moreover, an identical or very similar profile of cytokines is expressed during antigen-independent rejection. A cytokine-adhesion molecule cascade appears to underlie the development of chronic rejection. A means may be needed in order to allow permanent engraftment even in the event that graft tolerance is present.
T-cell activation, as emphasized by Boussiotis et al. (pp 797~807), involves at least three steps: adhesion of T cells and antigen-presenting cells (APCs), antigen recognition, and co-stimulation. Obviously, T-cell activation cannot occur in the absence of the direct cell to cell interaction of T cells and antigen-bearing APCs. Indeed, antigen recognition in the absence of co-stimulation leads to a long-lived state of antigen-specific hyporesponsiveness.
Donor-specific immune suppression can be produced in pre-clinical transplant models through pre- or peritransplant administration of donor hematopoietic cells or, as Krensky and Clayberger note, administration of whole donor MHC class I and perhaps MHC class II molecules. This research team began to explore the administration
Although cognate interaction of any of several pairs of cell surface APC and T-cell proteins leads to co-
Abbreviations APC-antigen-presenting
0 Current
Biology
cell; Th-T
helper.
Ltd ISSN 0952-7915
755
756
Transplantation
of select linear sequences of donor acute antigens to allograft recipients in order to aid engraftment. Given the diversity of the MHC, a dauntingly high number of reagents would be required to attempt to achieve allelespecific graft prolongation in the clinic. The a-1 alpha helix of MHC class I was singled out for special interest by Krensky and Clayberger. Other groups are also studying the use MHC class II sequences to prolong engrafiment of rat allografts. Early pre-clinical studies that explore the use of MHC peptides to abet engratiment of organ allografis are reviewed. The addition of cyclosporine to the conventional azathioprine and corticosteroid protocol has resulted in a great improvement in the rate of clinical organ engraftment. Much has been learned about the mechanisms by which these drugs impose their immunosuppressive effects. These refinements in our understanding of the basis of immunosuppressive effects have been reviewed by Sharma et al.. Other drugs are now under development; for example, FK506, whose ability to block the enzymatic function (phosphatase) of calcineurin, parallels that of cyclosporine. Recent experiments have revealed that cyclosporine induces expression of transforming growth factor p, a potent inhibitor of IL-2-driven T-cell proliferation. This interesting action may prove to be a critical aspect of the mechanism of action by which cyclosporine blocks allograft rejection. As discussed by Sharma ef al., several other interesting drugs including rapamycin, RS61443, mizoribine, deoxyspergualin and brequinar are undergoing evaluation in the clinic.
novel and highly creative therapeutic approaches to circumvent that problem and emphasize that once hyperacute rejection is solved, then control of the cellular immune response should be no more difficult than the problem encountered within allograhs. The problem of graft versus host disease has been a major constraint on the development of allogeneic marrow transplantation, whether for leukaemia or for a diverse range of benign blood disorders. Even though allo-reactive T cells have been known to be responsible for this syndrome, T-cell purging of marrow has still to establish itself as more advantageous than conventional drug immunosuppression. Waldmann et al. review the prospects for controlled purging of T cells and conclude that there may be more opportunities to improve the outcome of allogeneic marrow transplantation, by building on the benfits of marrow purging, than in maintaining the SU~MS quo.
The immunological foundations for developing new therapeutics in transplantation are becoming increasingly firmer, and the optimism of this set of current opinions should encourage immunologists to realise that the explosion in knowledge over the past 20 years is now coming to tiuition in terms of clinical applicability. We hope you agree!
Reference 1.
The scarcity of human organs for transplantation has led to large efforts to overcome the problems of xenografi rejection. The novel challenge in this area is that of overcoming hyperacute rejection elicited through inappropriate complement activation on the endothelial surface. Dorling and Lechler (pp 765-769) review the status of
Suthanthiran M, Strom TB: Renal Transplantation. 1994, 331:365-376.
TU Strom, Ueth Israel Hospital, Avenue, Boston, Massachusetts
N Eng / Med
Research East 319, 330 Brookline 02215-5491, USA.
H Waldmann, Sir William I>unn School Parks Road, Oxford OX1 3l
of Patholog,
South
Boston,
Massachusetts, USA and Sir William Oxford, UK
Current
Opinion
in Immunology
Refinements in immunosuppressive protocols and means to prevent and treat infectious diseases have led to a gratifiring improvement in successful short-term engraftment of allogeneic tissue and patient survival [l]. Nonetheless, unsolved problems abound in the field of transplantation. Although our immunosuppressive protocols have improved, they are still not able to universally prevent rejection and certainly do not uniformly create a state of graft tolerance. Indeed, the basic mechanisms underlying rejection (Nickerson et al., pp 757-764) or graft versus host disease (Waldmann et al., pp 777-783), and creation of the tolerance state have not been firmly established. Although our newer immunosuppressive protocols aIe vastly improved in their capacity to prevent or extinguish acute rejection (Sharma et al., pp 784-790, and Krensky and Clayberger, pp 791-796), we have made no headway in dampening the tempo of chronic rejection (Azuma and Tilney, pp 770-776).
1994,
Dunn School of Pathology,
6:755-756
stimulation in vitro, blockade of only the B7 to CD28 interaction produces anergy. For several years it has been known that B7 expressed on APCs can bind to either CD28 or CTLA4 T-cell surface proteins. More recent data, reviewed by Boussiotis et al., emphasize that at least two and probably three different B7 proteins exist. The expression of B7 proteins on various resting or stimulated cells may vary. Moreover, the signals imparted by individual B7 proteins may lead to very different outcomes on the nature of T-cell activation. It has also become clear that activation of CD28, a low-affinity site for B7-1, but not CTLA-4, a high-affinity site, leads to effective co-stimulation. There is potential for creating tolerance to alloantigens or autoantigens in the clinic through blockade of the CD28 pathway co-stimulation. As noted by Azuma and Tilney, improvements in immunosuppressive protocols and other aspects of clinical management have resulted in an enhanced rate of 1 year graft survival for kidney, pancreas, heart and liver transplants. Despite these improvements, the fate of grafts that are functioning well 1 year aftei&3nsplantation is precisely the same-as noted several decades ago. In short, the outlook for overcoming or preventing acute rejection has improved greatly while we have made no headway in preventing or treating chronic rejection.
Nickerson et al. review the data showing that antigenactivated CD4+ T cells can be subclassed on the basis of patterns of cytokine secretion. Many studies have indicated that the nature of the immune response to an antigen is strongly influenced by the profile of cytokines expressed by antigen-activated CD4+ T cells. Rejection is associated with vigorous expression of IL-2 and IFNy. In contrast, IL-2 and IFNy expression are markedly depressed in tolerized hosts, whereas expression of IL-4 is unimpaired or even enhanced. Is rejection necessarily mediated by the T helper (Th) 1 cells? Is tolerance caused by ‘unopposed’ Th2 cell activity?
Azuma and Tilney’s review emphasizes that both antigen-dependent and antigen-independent events can cause chronic rejection. The same type of pathologic changes are seen in both circumstances. Moreover, an identical or very similar profile of cytokines is expressed during antigen-independent rejection. A cytokine-adhesion molecule cascade appears to underlie the development of chronic rejection. A means may be needed in order to allow permanent engraftment even in the event that graft tolerance is present.
T-cell activation, as emphasized by Boussiotis et al. (pp 797~807), involves at least three steps: adhesion of T cells and antigen-presenting cells (APCs), antigen recognition, and co-stimulation. Obviously, T-cell activation cannot occur in the absence of the direct cell to cell interaction of T cells and antigen-bearing APCs. Indeed, antigen recognition in the absence of co-stimulation leads to a long-lived state of antigen-specific hyporesponsiveness.
Donor-specific immune suppression can be produced in pre-clinical transplant models through pre- or peritransplant administration of donor hematopoietic cells or, as Krensky and Clayberger note, administration of whole donor MHC class I and perhaps MHC class II molecules. This research team began to explore the administration
Although cognate interaction of any of several pairs of cell surface APC and T-cell proteins leads to co-
Abbreviations APC-antigen-presenting
0 Current
Biology
cell; Th-T
helper.
Ltd ISSN 0952-7915
755
756
Transplantation
of select linear sequences of donor acute antigens to allograft recipients in order to aid engraftment. Given the diversity of the MHC, a dauntingly high number of reagents would be required to attempt to achieve allelespecific graft prolongation in the clinic. The a-1 alpha helix of MHC class I was singled out for special interest by Krensky and Clayberger. Other groups are also studying the use MHC class II sequences to prolong engrafiment of rat allografts. Early pre-clinical studies that explore the use of MHC peptides to abet engratiment of organ allografis are reviewed. The addition of cyclosporine to the conventional azathioprine and corticosteroid protocol has resulted in a great improvement in the rate of clinical organ engraftment. Much has been learned about the mechanisms by which these drugs impose their immunosuppressive effects. These refinements in our understanding of the basis of immunosuppressive effects have been reviewed by Sharma et al.. Other drugs are now under development; for example, FK506, whose ability to block the enzymatic function (phosphatase) of calcineurin, parallels that of cyclosporine. Recent experiments have revealed that cyclosporine induces expression of transforming growth factor p, a potent inhibitor of IL-2-driven T-cell proliferation. This interesting action may prove to be a critical aspect of the mechanism of action by which cyclosporine blocks allograft rejection. As discussed by Sharma ef al., several other interesting drugs including rapamycin, RS61443, mizoribine, deoxyspergualin and brequinar are undergoing evaluation in the clinic.
novel and highly creative therapeutic approaches to circumvent that problem and emphasize that once hyperacute rejection is solved, then control of the cellular immune response should be no more difficult than the problem encountered within allograhs. The problem of graft versus host disease has been a major constraint on the development of allogeneic marrow transplantation, whether for leukaemia or for a diverse range of benign blood disorders. Even though allo-reactive T cells have been known to be responsible for this syndrome, T-cell purging of marrow has still to establish itself as more advantageous than conventional drug immunosuppression. Waldmann et al. review the prospects for controlled purging of T cells and conclude that there may be more opportunities to improve the outcome of allogeneic marrow transplantation, by building on the benfits of marrow purging, than in maintaining the SU~MS quo.
The immunological foundations for developing new therapeutics in transplantation are becoming increasingly firmer, and the optimism of this set of current opinions should encourage immunologists to realise that the explosion in knowledge over the past 20 years is now coming to tiuition in terms of clinical applicability. We hope you agree!
Reference 1.
The scarcity of human organs for transplantation has led to large efforts to overcome the problems of xenografi rejection. The novel challenge in this area is that of overcoming hyperacute rejection elicited through inappropriate complement activation on the endothelial surface. Dorling and Lechler (pp 765-769) review the status of
Suthanthiran M, Strom TB: Renal Transplantation. 1994, 331:365-376.
TU Strom, Ueth Israel Hospital, Avenue, Boston, Massachusetts
N Eng / Med
Research East 319, 330 Brookline 02215-5491, USA.
H Waldmann, Sir William I>unn School Parks Road, Oxford OX1 3l
of Patholog,
South