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SYMPOSIUM : New Approaches in Transplant Therapy |
*
Department of Medicine, Mount Sinai School of Medicine, New York, New
York
Department of Pediatrics, Stanford University School of Medicine,
Stanford, California.
Correspondence to Dr. Alan M. Krensky, Department of Pediatrics, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305-5208. Phone: 650-498-6073; Fax: 650-498-6077; E-mail: mn.aln{at}forsythe.stanford.edu
Abstract
Abstract. A growing body of experimental evidence demonstrates that synthetic peptides corresponding to linear sequences of MHC (HLA in humans) proteins have immunomodulatory effects in vitro and in vivo in animal models and in humans. Although the original concept was that these peptides inhibited antigen recognition at the MHC-T cell receptor interface via physical blockade, it is now clear that the mechanisms responsible for the myriad of functional effects are more complex. Recent findings show that some peptides affect signal transduction and cell cycle progression. Fragments of MHC molecules can dampen or downregulate immune responses via a variety of mechanisms. Some soluble MHC molecules or synthetic peptides are capable of inducing and maintaining immunologic tolerance in animals. This information suggests that synthetic peptides themselves or drugs mimicking their effects may represent a new class of immunotherapeutics.
In recent years, great strides have been made toward a more complete
understanding of the interaction between T cell receptors (TCR) and MHC
molecules. The three-dimensional structures of both MHC class I and II
molecules were determined by x-ray crystallography
(1,2).
Subsequently, the structure of two class I restricted TCR and their
interaction with MHC/peptide complexes were described
(3,4).
We now know that the extracellular portion of the MHC molecule is a
peptide-binding groove, with walls formed by two 
helices and a floor
consisting of eight ß-pleated sheets
(2,5).
The nature of the peptide bound to the MHC molecule is determined, in part, by
the MHC amino acid sequences concentrated within this groove. MHC
polymorphisms, therefore, confer spatial and charge constraints on binding
(2,6).
The peptide in turn can induce conformational changes on the MHC molecule
(7,8).
The resultant three-dimensional structure formed by the interaction of the
peptide and the MHC molecule is what is recognized by the TCR
(9). Interaction of the TCR
with the MHC molecule in the presence of the appropriate T cell costimulation
leads to T cell activation
(10). There is now substantial
evidence that the response of the T cell is not an "all or none"
response, but rather a qualitative one that may be altered by subtle changes
in the sequence of the MHC-bound peptide
(11,12).
This plasticity in T cell recognition can allow the activation of T cells by
peptides that are unrelated in sequence
(13,14),
whereas peptides that differ by as little as a single amino acid may alter the
pattern of phosphorylation initiated by interaction of the TCR with the
MHC/peptide complex, resulting in an altered activation state
(15).
In conjunction with our growing understanding of the nature of the T cell interaction with MHC, major advances have also been made in determining the pathways involved in recognition of alloantigen specifically (16). Overwhelming evidence points to the existence of two pathways of allorecognition: (1) The "direct" pathway, in which donor MHC is recognized by recipient T cells as an intact molecule with its associated peptide on the surface of donor antigen presenting cells (APC); and (2) The "indirect" pathway, in which recipient T cells recognize donor MHC as processed allopeptides presented in the context of self MHC (17,18) (Figure 1). It has been suggested that indirect allorecognition may be the dominant pathway mediating chronic allograft rejection (19,20). These developments underscore the pivotal role of peptides in allorecognition and highlight them as a potential strategy for altering the alloimmune response. Many studies have demonstrated an immunomodulatory role for MHC-derived peptides acting at several different stages in T cell activation and proliferation (Figures 2 and 3). The peptides used in these studies are summarized in Table 1 and are the subject of this review. The two main categories of peptides are MHC peptides derived from either conserved or nonpolymorphic areas of the MHC, and those that are derived from variable or polymorphic regions of the MHC. These two groups of peptides differ greatly in their receptors, modes of action, and specificities. They have in common, however, the advantage of the nontoxic nature of peptides and their potential to induce immunologic tolerance, the "holy grail" of transplantation immunology.
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Polymorphic MHC-Derived Peptides
Much of our understanding of the indirect pathway of allorecognition has been gained through use of synthetic polymorphic peptides derived from both class I and class II MHC sequences. Self-MHC-restricted recognition of processed allo-MHC peptides occurs during both vascularized cardiac (21,22) and renal allograft rejection (23). Induction of transplantation tolerance through manipulation of the indirect pathway has been possible after intrathymic administration of these immunogenic peptides. Shirwan et al. (22) showed that tolerance to rat cardiac allografts can be induced after intrathymic injection of class I MHC allopeptides into a class I MHC disparate strain combination. Long-term unresponsiveness after intrathymic administration of class I MHC allopeptides is associated with a state of immune deviation, with increased intragraft expression and serum levels of Th2 cytokines (24). Ohajekwe et al. demonstrated that thymic tolerance could still be affected with administration of alloantigens posttransplant in combination with low doses of antilymphocyte serum (25). Sayegh et al. induced donor-specific tolerance in a rat renal allograft model by administration of synthetic peptides representing full-length hypervariable regions of two different rat class II MHC sequences (26). Long-term engraftment could be produced only by those peptides that were immunogenic (27). Studies of the mechanisms of acquired thymic tolerance to renal allografts by class II MHC allopeptides indicate that the induction phase is dependent on the presence of an intact thymus and is mediated by peripheral T cell anergy. In contrast, the maintenance phase is not dependent on the thymus and may be mediated by clonal deletion of specific alloreactive T cell clones (27). Orally administered synthetic class II MHC allopeptides also have tolerogenic effects and can inhibit delayed-type hypersensitivity (28). Only immunodominant peptides are tolerogenic, and the unresponsive state is associated with a state of immune deviation to a predominance of Th2 cell function (28,29).
The induction of tolerance to allografts has been achieved by the
development of "allochimeric" proteins in which polymorphic
regions of donor class I MHC are incorporated into a backbone of the recipient
class I MHC. Initial experiments by Ghobrial et al. involved
transfecting hepatoma cells with a chimeric sequence produced by a PCR-based
method of gene splicing (30).
The amino acid sequence corresponding to residues 58 to 80 of one strain,
including 10 polymorphic residues, were incorporated into another class I MHC
1-helical region. Subcutaneous administration of the
transfectants that produce a soluble form of the chimeric MHC protein resulted
in accelerated rejection of cardiac allografts. In contrast, subcutaneous
administration to another strain of rat caused significant prolongation of
allograft survival. A more striking effect was seen after a single intraportal
injection in conjunction with subtherapeutic cyclosporine. A baculovirus
expression system was used to produce chimeric proteins, in which the
nucleotides encoding the polymorphic amino acids from one class I MHC
1-helix were substituted into the
1-helical region of another strain
(31). These chimeric proteins
had differing effects on survival of cardiac allograft depending on the amino
acid substitutions. A single intraportal injection of some peptides at the
time of transplant had no effect on graft survival, while one peptide produced
long-term survival in four of six animals. The immunomodulatory effect
required coadministration of low-dose cyclosporine. Thus, peptides derived
from MHC class I sequences incorporating specific donor amino acid
substitutions can be processed and presented by recipient APC. These
"neoantigens" can induce long-term engraftment.
Because peptides binding to the same MHC class II molecule can compete with each other for presentation to T cells, priming of T cells may be inhibited in vivo by coadministration of antigen and a molar excess of a competitor peptide (32). This raises the possibility of inducing selective immunosuppression by blocking the binding site of the class II molecule, so-called "MHC blockade." Harris et al. demonstrated that the proliferative response of a T cell line specific to a peptide corresponding to residues 21 to 42 of an HLA class II molecule could be inhibited by an excess of peptide 43 to 62 from a relatively nonpolymorphic region of the same allele (33). Guery et al. prevented priming in vivo by immunizing with an immunogenic peptide derived from hen egg lysozyme with restricted presentation competed out by endogenous mouse lysozyme restricted to the same MHC class II molecule (34). This method has been successful in vivo in several autoimmune models, including experimental allergic encephalomyelitis (EAE) (35,36) and autoimmune diabetes (37).
Inhibition of the T cell response with antigen analogs in which the major T cell contact residues have been modified can produce powerful antagonists. In this case, the peptide does not interfere with the TCR/APC interaction; rather, early events in T cell activation are inhibited (34). Indirect recognition of allopeptides in acute transplant models is restricted to a limited number of immunogenic peptides (21,23,38). In addition, responding T cells show restricted TCR Vß usage (39,40,41). The potential therefore exists to inhibit the alloimmune response through TCR antagonism. Colovai et al. induced specific suppression of indirect allorecognition in human T cell clones with analogs of immunogenic allopeptides in which critical TCR/MHC+peptide contact residues were changed (42). TCR antagonism can prevent disease in an EAE model (43).
Another potential mechanism is "high zone" tolerance, in which
high concentrations of antigen stimulate initial T cell activation followed by
cell death. Liu et al. demonstrated this effect in an in
vitro human system (44).
Using T cells from a DRB1*1101, 0701 responder primed to a
genetically engineered DR4 molecule, they found proliferation to a single
peptide (residues 69 to 88) presented in the context of DRB1*1101.
Complete suppression of proliferation of the T cell lines could be obtained by
a ninefold increase in the concentration of this peptide in culture. This
effect was associated with absence of production of interleukin-4 (IL-4) but
no difference in the production of IL-2. Similar findings have been
demonstrated in EAE, in which high concentrations of myelin basic protein are
associated with activation-induced apoptosis of reactive T cells and a
concomitant decrease in incidence and severity of disease
(45). Administration of a
monoclonal antibody to the -chain of the IL-2 receptor protected T
cells from antigen-induced death in vitro, and IL-2 enhanced the
effect in vivo.
Nonpolymorphic Class I MHC Peptides
Synthetic peptides representing relatively nonpolymorphic regions of class I MHC sequences have immunoregulatory effects both in vitro and in vivo. Schneck et al. demonstrated that a peptide derived from residues 163 to 174 of a murine MHC class I molecule, a potential site for interaction with TCR, inhibited lysis of targets by allogeneic cytotoxic T lymphocytes (CTL) (46). Pretreatment of the T cell and not the APC with peptide resulted in inhibition of CTL cytotoxicity. This peptide appears to interfere with TCR engagement at the contact site on the MHC molecule.
Initial studies by Clayberger et al. showed that synthetic
peptides corresponding to certain polymorphic regions of the
1 or 2 domain of HLA-A2 inhibited lysis by
CTL by competing with the specific allele for binding to the TCR
(Figure 4)
(47,48).
The clinical value was limited, however, by the allele-specific nature of this
inhibition. Additional studies demonstrated that synthetic peptides
corresponding to residues 222 to 235 of the HLA class I sequence, the CD8
binding loop, were able to inhibit CTL differentiation, but they did not
affect cytolysis by mature CTL
(49). Subsequent studies
focused on peptides derived from a conserved region of the 1
domain of the human class I MHC, which were shown to inhibit class I
restricted immune responses in an allele nonspecific manner. These effects
were attributed to residues 75 to 84 of the 1 helix of HLA
class I molecules expressing the Bw4a public determinant. HLA-B7.75-84 and
HLA-B2702.75-84 peptides (ALLOTRAPTM peptides, Sangstat Medical Corp.,
Menlo Park, CA) prevented the differentiation of precursors into effector CTL
in vitro, inhibited lysis by established CTL, and inhibited natural
killer cell-mediated cytotoxicity
(50).
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These peptides have immunomodulatory effects in vivo in several animal models. The original report from Nisco et al. showed that administration of the HLA-B7.75-84 peptide in conjunction with a subtherapeutic dose of cyclosporine resulted in indefinite graft survival in 75% of rat cardiac allografts recipients (51). Long-term surviving animals were specifically tolerant, since they accepted a second heart or skin transplant from the same donor while rejecting that from a third party. Administration of the peptide alone in a weaker responder-stimulator strain combination resulted in prolongation of cardiac allograft survival rather than tolerance (52). Buelow et al. investigated the effect of four HLA-derived peptides (residues 75 to 84) on rejection of skin allografts in a mouse model (53). HLA-B2702.75-84 significantly prolonged graft survival when given alone or in combination with cyclosporine. HLA-B7.75-84, in contrast, did not significantly alter graft survival. HLA-B2702.75-84 also induced long-term graft survival in 60% of mouse cardiac allograft recipients (54) and significantly prolonged small bowel allograft survival (55) when given in combination with low-dose cyclosporine. In a rat cardiac chronic rejection model, treatment with alternate day HLA-B7.75-84 plus low-dose cyclosporine produced prolonged graft survival and inhibited the development of transplant arteriosclerosis (56). More recent data showed that the D-isomer, which is more resistant to proteolytic breakdown, is more potent than the original L-isomer peptide (57).
On the basis of these encouraging results in animal models, a randomized, double-blind, placebo-controlled study of the safety and the pharmacokinetics of HLA-B2702.75-84 in human recipients of a first renal allograft was conducted (58). Patients received a dose of 7 mg/kg administered immediately after transplantation and at 24-h intervals thereafter varying from two doses to 10 depending on the treatment group. There were no toxic effects during the 3-mo follow-up. No phenotypic differences were found in the lymphocyte population after administration of HLA-B2702.75-84 compared with placebo. However, in those patients that received a 10-d treatment, there was a significant reduction in natural killer cell cytotoxicity noted from day 15 through 2 mo after the end of treatment. This prolonged effect occurred despite the fact that the half-life of the parent compound was only 20 min. This reduction in natural killer cell activity is consistent with in vitro data in humans (50) and in vivo findings in animals (52). The clinical significance of these results is uncertain, although they are the first example of an in vivo effect of an HLA-derived peptide in humans. In fact, there was a tendency toward more acute rejection episodes and viral infections in the treatment groups. Interestingly, those patients in whom a rejection episode did occur showed no significant difference in natural killer cell cytotoxicity when compared to patients with no rejection episodes. The rational design of analogs of this first-generation therapeutic are in progress (Sangstat Medical Corp.).
Noessner et al. investigated the mechanism of action of this group of peptides. They demonstrated that HLA-B2702.75-84 and its inverted dimer bound to two proteins of molecular weight 70 and 74 kD from T cell lysates. These proteins are members of the heat shock protein (HSP) 70 family (59). Peptide binding to HSP70 proteins correlated with inhibition of human CTL cytotoxicity and could be attributed to the presence of positively charged residues at positions P2, P4, and P6. Noninhibitory peptides lacked this binding motif. Furthermore, amino acid substitution at residue 80 in HLA-B2702.75-84 resulted in significantly reduced binding and a loss of functional activity. On the basis of these results, it was postulated that the class I HLA-derived peptides act intracellularly by binding to HSP in a manner similar to the binding of cyclosporine and FK506 to cyclophilin and FK506 binding protein, respectively.
More recent studies, in which the effects of a panel of peptides on CTL-mediated cytotoxicity, graft survival, and binding to HSP70 were examined, indicate that their immunomodulatory activity correlated poorly with binding to HSP70. D-isomers of the original inhibitory peptides proved more effective at inhibiting CTL cytotoxicity while showing no binding to HSP70 (60). There is now evidence that the D-isomer of HLA-B2702.75-84 may function by binding to HSP32 or heme oxygenase-1 (HO-1), an inducible HSP (61). In addition, activity of individual immunomodulatory peptides correlates with inhibition of HO-1 in vitro and the induction of HO-1 in vivo. HO-1 catalyzes the metabolism of heme to biliverdin, which is subsequently reduced to bilirubin. It has been suggested that HO-1 exerts its effects through these intermediate metabolites, which are immunoregulatory in their own right. They inhibit complement, IL-2 production, anti-body-dependent and -independent cell-mediated cytotoxicity, and proliferative responses (61).
Nonpolymorphic Class II MHC-Derived Peptides
Many naturally processed peptides bound in the groove of cell surface MHC class II molecules are derived from highly conserved regions of both class I and class II MHC sequences (62,63). This observation raises questions about the role of these peptides. Do they simply function as a means to stabilize the heterodimer for presentation on the cell surface or do they have a specific immunomodulatory role? Both of our groups have investigated the ability of peptides derived from conserved regions of the MHC class II molecule.
Boytim et al. demonstrated that a synthetic peptide corresponding
to the 1 -helix of DQA03011(DQ 65-79) inhibits anti-CD3
monoclonal antibody (mAb), mitogen, and alloantigen-induced T cell
proliferation in an allele-independent manner
(64). Delayed addition of the
peptide up to 24 h after stimulation with anti-CD3 has a minimal effect on
inhibition. In addition, inhibition of anti-CD3 mAb-induced proliferation is
not reversed by anti-CD28 mAb or IL-2. Cells that were initially stimulated in
the presence of DQ 65-79 are unresponsive to restimulation. The activity of
this peptide is enhanced by serine substitutions at residues 70 and 74, while
substitutions at 65 and 67 maintain activity. All other substitutions abrogate
the immunomodulatory role of DQ 65-79. To determine the potential site of
action of DQ 65-79, its effects on early gene expression and cell surface
receptor expression were examined. The levels of CD2, CD4, CD8, MHC class I
and II, and IL-2R CD69 and CD45RO were identical in experimental and control
groups. Cell cycle analysis showed that the peptide prevented DNA replication
by blocking the G1 to S transition, suggesting that the peptide may
work in a manner similar to rapamycin. This was confirmed by the finding that
DQ 65-79 inhibited cyclin-dependent kinase 2 via a block in the degradation of
the inhibitory protein p27. The effects, however, unlike rapamycin, are not
mediated through binding to FK506 binding protein since the peptide did not
compete for binding with FK506. Recently, a yeast two-hybrid system was used
to identify cellular receptor(s) for the peptide
(65). This approach identified
proliferating cell nuclear antigen (PCNA) as a DQ 65-79 binding protein and
suggests that the peptide interferes with the normal interaction of cyclins,
cyclin-dependent kinases, and PCNA.
Murphy et al. initially studied the immunomodulating effects of
rat synthetic class II MHC peptides in vitro
(66). They demonstrated that a
peptide derived from the nonpolymorphic rat MHC class II (RT1.Du)
chain (residues 51 to 75) inhibited mixed lymphocyte reaction (MLR)
and CTL generation in a dose-dependent manner. This inhibition was neither
strain- nor species-specific. Further experimentation indicated that the
active peptide is a 15-mer and corresponds to residues 61 to 75. More recent
studies compared the immunomodulatory capabilities of this 15-mer peptide with
those of three additional peptides. Two of these peptides,
HLA-DQA*0101 and HLA-DQB1*0501, correspond to the same
region (i.e., residues 62 to 77) of the human class II MHC, and the
third, RT1.B, corresponds to the same region of the rat class II MHC
DQ-like allele. Those peptides derived from the chain were found to
inhibit the rat MLR in a dose-dependent manner. The most potent peptide was
the human HLA-DQ. This sequence was also found to be an efficient
inhibitor of human and mouse MLR. Its effect was, therefore, neither strain-,
allele-, nor species-dependent. HLA-DQB1*0501 peptide, which had no
inhibitory effect, was subsequently used as a control peptide.
HLA-DQA*0101, but not HLA- DQB1*0501, peptide inhibited
cytotoxic T cell generation in a dose-dependent manner, whereas neither
peptide affected preformed effector cytotoxic T cells. This indicated that the
inhibitory effect is targeted at CD4+ T helper function.
HLA-DQA*0101 had no effect on mitogen-induced proliferation, but it
did inhibit proliferation to superantigen, suggesting that it interferes with
the TCR-MHC interaction. Cytokine analysis of human MLR supernatants by
enzyme-linked immunosorbent assay showed complete suppression of
interferon-
and IL-2 production by HLA-DQA*0101.
HLA-DQA*0101-mediated inhibition of proliferation to alloantigen is
partially reversed by IL-2, but it is completely reversed by anti-CD28 mAb
(67). The immunomodulatory
effects of this peptide are mediated through induction of apoptosis in
activated T cells. Interestingly, HLA-DQA*0101
(62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77)
is derived from the same region but a different allele as the peptide studied
by Boytim et al. (Figure
5). Despite this parallel structural origin, the mechanisms of
action of these two peptides appear to be remarkably different. Nevertheless,
both peptides dampen or downregulate the immune response.
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Peptide Inhibitors of CD4/CD8 Coreceptor Interactions
As noted above, Clayberger and colleagues showed that a synthetic peptide corresponding to the CD8 binding loop of HLA class I inhibited the generation of CTL but failed to block killing by established CTL (49). This finding coincides with our current understanding of the role of CD8 in early stages of T cell activation rather than adhesion per se. They further showed that peptides corresponding to a CD4 binding region of class II MHC (residues 134 to 152 of HLA-DR-ß chain) inhibited differentiation of CTL precursors, proliferation by peripheral blood lymphocytes, and proliferation by an antigen-specific CD4+ T cell clone. Shen et al. confirmed that peptides corresponding to the CD4-interacting region on the MHC class II-ß chain can interfere with T helper function and extended these findings to an in vivo situation. Although these peptides were inhibitory at high doses, they were stimulatory at lower doses (68). Results such as these, that disruption of crucial protein-protein interactions can be used to alter the immune response, led to the application of newer computer-based strategies and molecular modeling techniques to rationally design analogs with an immunomodulatory effect.
Jameson et al. targeted the MHC class II-CD4 interaction site with
a synthetic structure-based, designed peptide. This peptide corresponds to
residues 86 to 94 of the mouse CD4 molecule, the complementary determining
region 3-like portion of CD4
(69). This peptide was
synthesized with D-amino acids in an attempt to make it more resistant to
protease degradation. This necessitated that the peptide was synthesized in
reverse order so as to maintain a similar orientation of side chains compared
with the original molecule. In addition, a proline-glycine-proline-cysteine
sequence was added to allow tertiary structural constraints and cyclization.
The peptide is referred to as rD-mPGPtide. Initial experiments showed that
treatment with rD-mPGPtide resulted in reduction in incidence and severity of
disease in EAE. This was effective when administered at the early or late
induction phase and, importantly, during the late effector phase when disease
was already established
(69,70).
This effect is specific and responses to other antigens remain intact. Unlike
anti-CD4 mAb, rD-mPGPtide does not cause CD4 depletion, and it is not
immunogenic. With regard to alloreactivity, this peptide analog has
significant effects in both bone marrow and skin transplant models. Treatment
with rD-mPGPtide prolonged survival in acute graft-versus-host
disease (GVHD) across MHC barriers, prevented the development of GVHD mediated
by MHC allogeneic CD4+ T cells, and prolonged engraftment. T cells from
treated animals were hyporesponsive with greater than 50% reduction in MLR.
This effect was specific since cells stimulated by third party cells
responded. Furthermore, animals challenged with donor strain skin grafts did
not reject, whereas third party skin grafts were rejected in a normal manner
(71,72).
The concomitant use of cyclosporine and rD-mPGPtide had enhanced effects over
either agent alone, and the combination allowed a reduction in the dose of
cyclosporine used (73). This
has important implications with regard to cyclosporine side effects,
particularly nephrotoxicity. rD-mPGPtide also enhances skin allograft survival
between MHC class II disparate strain combinations
(74). This was associated with
a reduction in the precursor frequency of alloreactive T cells and a
downregulation in the production of IL-2 and interferon-. The exact
mechanism mediating the inhibitory effect of rD-mPGPtide on CD4 function is
unclear. One proposed mechanism is that it acts by uncoupling CD4-CD4
dimerization, which may be required for stable interaction between the MHC
molecule and TCR. This would interfere with T cell signaling required for
activation.
A compound that mimics the CD4 surface pocket contributed by domain 1 of the CC' loop was produced based on nuclear magnetic resonance data (75). This compound, referred to as cyclic hexapeptide IV, inhibited CD4 activation and modulated the response in three CD4+ T cell-dependent mouse models, EAE, skin allograft rejection across an MHC class II antigen difference, and GVHD across a haplomismatched MHC difference. This group also used computer-based strategies to develop other compounds that target the interaction of MHC class II with CD4. One family of nonpeptide organic compounds (TJU101-104) inhibited the MHC class II-CD4 interaction in a dose-dependent manner by docking in the CD4 surface pocket, preventing binding of MHC class II (76). All four compounds had immunomodulatory effects in both allo- and autoimmune animal models in vivo. The use of computer and modeling technologies in conjunction with our expanding understanding of structure-function relationships offer exciting opportunities for development of new immunomodulatory agents.
MHC Class II-Associated Invariant Chain Peptide
MHC class II-associated invariant chain peptide (CLIP) is essential for proper loading of exogenous peptide on MHC. It stabilizes the heterodimer and permits presentation of MHC class II with its associated antigenic peptide on the cell surface. On the basis of this premise, Zechel et al. synthesized a peptide with a sequence derived from CLIP. This peptide inhibited antigen-specific T cell responses in vitro and in vivo following immunization. It is presumed to exert its effect through inhibition of loading of MHC with antigenic peptide (77). These results have not yet been extended to a transplant model.
Conclusion
There is now extensive evidence that synthetic peptides corresponding to linear MHC sequences are effective immunoregulators, targeting the immune response at many different sites. The nature of their effects can be broadly differentiated on the basis of whether the peptides are polymorphic, producing specific antigenic unresponsiveness, or nonpolymorphic, inducing more general immunomodulatory effects. These peptides offer the opportunity to develop a new class of immuno-therapeutics. Some appear capable of inducing and maintaining immunologic tolerance. Important issues regarding exact mechanisms of action, routes of administration, bioavailability, and the potential for combination therapies require further evaluation. Through pharmaceutical advances, including molecular modeling and chemical optimization, it is likely that first-generation peptides will be altered so as to enhance their effects or minimize their susceptibility to degradation. Peptides also serve to highlight potential molecular and pathway targets for future immunomodulation. We are at the start of an exciting new era. The observations to date using MHC-derived peptides can be expected to lead to the design of new drugs useful for the prevention and treatment of autoimmune diseases and transplant rejection.
Acknowledgments
Acknowledgments
This work was supported by NIH KO8 AI01538 to BM and PO1 AI41520 to AMK. AMK is the Shelagh Galligan Professor of Pediatrics and a Burroughs Wellcome Scholar in Experimental Therapeutics.
Footnotes
American Society of Nephrology
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