Current Drug Targets - Cardiovascular & Haematological Disorders, Volume 2, Number 2, 2002
Contents
Novel
Agents in Organ Transplantation
Guest Editor: Robert Zhong
Small Molecule
Immunosuppressive Agents in Experimental and Clinical Transplantation Pp.57-71
Anlun Ma
and Huifang Chen
New Immunosuppressants
in Clinical Trial Pp.73-77
Vivian C.
McAlister
Pharmacotherapeutic Approach to Prevent or
Treat Chronic Allograft Nephropathy Pp.79-96
E.M. Scholten, J.W. de Fijter and L.C. Paul
Novel Immunosuppressive
Agents in Tolerance Induction Pp.97-103
N.R. Krieger and S.J. Knechtle
Therapeutic Interventions In Xenotransplantation Pp.105-119
C. Knosalla, B. Gollackner, F.J.M.F.
Dor and D.K.C. Cooper
Abstracts
[Back to top] Small Molecule Immunosuppressive Agents in Experimental and Clinical
Transplantation
Immunosuppression is currently the major approach used for the prevention and management of transplant rejection. In this overview, preclinical and clinical studies of the small molecule immunosuppressive agents are reviewed from the discovery of cyclosporine. More recently it was demonstrated that certain agents, namely tacrolimus (FK506), sirolimus (rapamycin), and mycophenolate mofetil (CellCept, MMF), act selectively on adaptive host responses at different stages of T- and B-cell cycles and spare nonspecific host resistance. Because each agent has its specific and significant toxic effects, it has been difficult to optimize the use of individual agents in monotherapy. Therefore, drug combination therapy has been of great interest in addition to the introduction of new small molecule agents, such as malononitrilamides [MNAs (leflunomide, FK778, FK100%)], 15-deoxyspergualin (DSG) and its analogues, FTY720 and inhibitors of signal transduction, which offer promising modes of immunosuppression.
[Back to top] New Immunosuppressants
in Clinical Trial
Chemical immunosuppression developed at the beginning of clinical transplantation remains the basis of immunosuppressive protocols used today. Clinical trials of new agents focus on the incremental improvement in one of four areas of immunotherapy: induction, basic maintenance, adjuvant and steroid therapy. Induction immunotherapy developments include the use of humanized antibodies, specific targets (basiliximab, daclizumab) and lymphocyte depletion (anti-thymocyte globulin, campath-1H). Promising results from pilot trials allow for subsequent low dose maintenance monotherapy. New inhibitors of calcineurin isoforms (ISATx247) may disassociate the anti-rejection effect from the toxicity of conventional calcineurin inhibitors. Revived investigation of older anti-proliferative or anti-metabolite drugs (rapamycin, mycophenolic acid, leflunomide) show promise in preventing B-cell responses and reducing chronic rejection but development of derivatives (everolimus, mycophenolate mofetil, ERL 080, MNA 279, MNA 715) may have a stronger commercial than experimental basis. Trials of steroid immunotherapy have focused on steroid elimination but trial of newer locally active steroids may be beneficial.
[Back to top] Pharmacotherapeutic Approach to Prevent or Treat Chronic
Allograft Nephropathy
In the current paper we will review the evidence that drug therapy may be of value to prevent or treat chronic allograft nephropathy. We will review the immunosuppressive therapy and non-immune therapies in use to treat risk factors associated with chronic allograft nephropathy and evaluate their efficacy with respect to long term outcome as well as their effect on markers of long-term survival. In the last part of this review, we will indicate possible benefits of new approaches being explored but most of these data are obtained in in vitro test systems and rodent models.
[Back to top] Novel Immunosuppressive Agents in Tolerance Induction
N.R. Krieger and S.J. Knechtle
Induction of transplantation tolerance remains a much sought-after but elusive goal with a potential promise of rendering patients free of long-term immunosuppressive drugs while maintaining good organ transplant function indefinitely. All currently studied strategies toward transplantation tolerance include using immunosuppressive agents for a limited time period to achieve tolerance. There are a growing number of agents that lend themselves to tolerance induction and these agents are considered herein. Such agents generally fall into the categories of lymphocyte depletion, costimulation blockade, and adjunctive agents such as rapamycin. Preliminary data using donor stem cells suggests that embryonic stem cells may have substantial advantages over conventional donor
bone marrow for tolerance
induction. These preliminary results are briefly reviewed as well. Tolerance
has been achieved in a small number of organ transplant patients and such
successes suggest that progress in the clinical arena is happening and is an
obtainable result.
[Back to top]
Therapeutic
Interventions In Xenotransplantation
Xenotransplantation,
involving the transplantation of pig organs into humans, would resolve the
current shortage of organs. It involves, however, a new therapeutic approach to
organ transplantation. The presence of natural antibody in primates directed
against Galá1,3Gal epitopes on pig vascular
endothelium leads to early antibody-mediated rejection. An elicited antibody
response against the same target epitopes as well as
against nonGal antigens intensifies the immune
destruction of the organ. Even the minimal deposition of antibody appears to
lead to the development of a consumptive coagulopathy
that can be fatal. Approaches being investigated to overcome these barriers
include depletion and inhibition of natural antibody and complement, and
suppression of the elicited T cell-dependent antibody and cellular responses.
In addition, however, physiologic incompatibilities between human and pig,
particularly those relating to coagulation, may enhance or complicate the
immune process, and may require additional therapeutic measures. Current
approaches aimed at achieving successful xenotransplantation
also include investigation of agents that prevent potential xenozoonotic
infection of the recipient. At present, therefore, the therapeutic
interventions required to attempt to overcome the barriers to xenotransplantation are multiple. Work indicating progress
in the breeding of pigs that do not express the critical Galá1,3Gal epitopes, however, is encouraging. The introduction of
these pigs may greatly reduce the therapy required, and may ultimately allow
the development of methods to induce tolerance to the transplanted pig organ.