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Ann Thorac Surg 1998;65:144-148
© 1998 The Society of Thoracic Surgeons

Original Articles: Cardiovascular

Induction of Tolerance in Rodent Cardiac Allotransplantation Using an MHC Class I-Derived Peptide and Cyclosporin A

Saqib Masroor, MD, Silviu Itescu, MD, John H. Artrip, MD, Oktavijan P. Minanov, MD, Roland Buelow, PhD, Robert E. Michler, MD

Cardiac Transplantation Research Laboratory, Division of Cardiothoracic Surgery, Columbia-Presbyterian Medical Center, New York, New York, USA

Accepted for publication July 15, 1997.


   Abstract
Top
 Abstract
Introduction
 Material and Methods
 Results
 Comment
 References
 
Background. The synthetic peptide corresponding to residues 75-84 of the human major histocompatibility complex class I molecule HLA-B7 (Allotrap 07) has been shown to inhibit differentiation of cytotoxic T lymphocyte precursors. Subsequent treatment of LEW-1A rats with this peptide was associated with a reduction in the level of cytotoxic activity directed to donor alloantigens. This study was undertaken to investigate the effect of Allotrap 07 on rodent heart allograft survival in LEW-1A recipients.

Methods. Heart allografts from Lewis rats were heterotopically transplanted into the infrarenal abdominal aorta of ACI recipients. The treatment groups consisted of different regimens of short-term intravenous Allotrap 07 and oral cyclosporin A. All grafts were palpated daily, with rejection defined as the cessation of palpable contractions.

Results. Cardiac allografts transplanted from Lewis to ACI rats survived indefinitely after administration of intravenous Allotrap 07 and oral cyclosporin A. Tolerance induction was donor-specific because third-party Brown-Norway, but not Lewis, grafts were rapidly rejected after implantation into ACI recipients.

Conclusions. Because donor-specific tolerance persisted long after cessation of peptide administration and did not occur when cyclosporin A was omitted from the immunosuppressive regimen, the mechanism may involve induction of clonal anergy.


   Introduction
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 Abstract
 Introduction
Material and Methods
 Results
 Comment
 References
 
Organ transplantation is often the only hope of survival for many individuals with end-stage organ failure. Despite the development of new surgical techniques and immunosuppressive drugs, graft rejection remains the primary complication of transplantation. At present, transplant recipients receive nonspecific immunosuppression with agents such as cyclosporin A (CsA) and azathioprine, which must be administered throughout the patient’s lifetime. Such prolonged immunosuppression has produced a significant incidence of opportunistic infections, malignancies, and drug toxicities in transplant recipients [1][2][3][4]. As a result, it has been the ultimate goal of transplant physicians to devise a therapeutic strategy that would induce donor-specific graft tolerance in the recipient while maintaining the ability to mount an immune response against tumors and infectious agents.

One promising therapeutic strategy has been the development of synthetic major histocompatibility complex (MHC) peptides. Synthetic peptides corresponding to polymorphic regions of the alpha 1 and alpha 2 domains of certain MHC class I molecules have been shown to block lysis by cytotoxic T lymphocytes (CTL) specific for the MHC molecule from which the peptide was derived [5][6][7]. Residues 75-84 of the alpha 1 chain constitute a less polymorphic and more conserved region of the human leukocyte antigen (HLA) class I molecule. Only ten variations have been found in more than 85 HLA-A, -B, and -C sequences determined to date [8]. Synthetic peptides corresponding to residues 75-84 of human HLA-B7 and HLA-B27 have been shown to block differentiation of CTL presursors [9]. These peptides have been marketed for research under the commercial name of Allotrap 07 and Allotrap 2702 (derived from residues 75-84 of the alpha 1 domain of human HLA-B7 and -B27, respectively). This study was undertaken to investigate the effect of Allotrap 07 (Allotrap) on rodent heart allograft survival.


   Material and Methods
Top
 Abstract
 Introduction
 Material and Methods
Results
 Comment
 References
 
Animals
Adult male ACI (RT1a) rats weighing 200 to 250 g (Charles River, Boston, MA) served as recipients of adult male Lewis (RT11) hearts (Charles River). Animals were acclimatized for at least 1 week before induction into the experimental protocol. All animal care and surgical procedures were approved by Columbia University’s Institution of Animal Care and were in compliance with the "Guide for the Care and Use of Laboratory Animals" published by the National Institutes of Health (NIH publication 85-23, revised 1985).

Organ Transplantation
Heart allografts from Lewis rats were heterotopically transplanted into the infrarenal abdominal aorta of ACI recipients using a modification of the technique described by Ono and Lindsey [10]. All grafts were palpated daily, with rejection defined as the cessation of palpable contractions. Rejection was confirmed by palpation under anesthesia and at celiotomy.

Immunosuppressive Regimen
Cyclosporin A (Sandoz Pharmaceuticals Corp, Basel, Switzerland) was administered orally through a gavage tube at a dose of 10 mg · kg-1 · day-1 on days 0 to 4 according to the prescribed schedule listed below. Allotrap 07 (a gift of Sangstat Corporation, Menlo Park, CA) was dissolved in sterile normal saline solution to achieve a concentration of 40 mg/mL and given at a dose of 40 mg · kg-1 · day-1 according to the prescribed schedule listed below.

Experimental Protocol
Animals were divided into the following groups:

  1. Untreated controls.
  2. CsA (oral) on days 0 to 4
  3. Allotrap (intravenous) on days -14, -12, -10, -7
  4. Allotrap (intravenous) on days 0, 2, 4, 6, 12
  5. Groups 2 + 3
  6. Groups 2 + 4
  7. Group 2 + Allotrap (intravenous) on days 0 to 4
  8. Group 2 + Allotrap (intraperitoneal) on days -14, -12, -10, -7

Statistical Analysis
Allograft survival is reported both as a mean ± standard error of the mean (days) and median (days). The data were analyzed with the Kruskal-Wallis one-way nonparametric analysis of variance. Pairwise comparisons were performed with the Wilcoxon rank sum test. Statistical significance was attributed to a p value of less than 0.05.


   Results
Top
 Abstract
 Introduction
 Material and Methods
 Results
Comment
 References
 
Effects of Pretransplantation Allotrap and Cyclosporin A
Untreated recipients (group 1) of Lewis heart allografts survived a mean of 9.75 ± 0.75 days (Table 1). Low-dose CsA (group 2) administered alone on days 0 to 4 after transplantation produced a significant prolongation in mean survival (30.3 ± 17.4 days). Pretransplantation intravenous administration of Allotrap alone (group 3) on days -14, -12, -10, and -7 did not prolong survival beyond that seen in untreated controls. In addition, posttransplantation intravenous administration of Allotrap alone (group 4) on days 0, 2, 4, 6, and 12 similarly did not prolong survival beyond that seen in untreated controls.


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  		Allograft Survival

 
Combination therapy using intravenously administered Allotrap before transplantation and CsA (group 5) did not prolong allograft survival beyond that seen with CsA alone (18.9 ± 6.5 versus 30.3 ± 17.4 days) and, in fact, eliminated the benefit seen with just CsA. However, combination therapy using CsA and posttransplantation intravenous Allotrap on days 0, 2, 4, 6, and 12 (group 6) resulted in significant prolongation of cardiac allograft survival (168.9 ± 61 days), with 6 of 8 grafts achieving tolerance (>200-day survival). Shortening the course of Allotrap treatment to days 0 to 4 in combination with CsA (group 7) significantly reduced allograft survival in comparison with the longer course of Allotrap (group 6). The shorter course of Allotrap (group 7) did not significantly prolong allograft survival beyond that seen with CsA alone (group 2) despite 2 of 8 grafts surviving beyond 200 days. Intraperitoneal Allotrap administered before transplantation in combination with CsA (group 8) prolonged mean graft survival to 87 ± 95.5 days, with 3 of 8 grafts surviving indefinitely (>200 days); however, this did not reach statistical significance when compared with CsA-treated animals (group 2).

Induction of Donor-Specific Tolerance
A second heart transplant procedure was performed on 6 animals that had retained their original grafts for more than 200 days. No further immunosuppression was administered after the second heart transplantation, and the original Lewis graft was left in place. Second-party Lewis allografts (n = 3) survived more than 100 days whereas third-party Brown-Norway allografts (n = 3) were rejected by day 12 (Table 2). The rejection of the third-party Brown-Norway allograft did not affect the function of the original Lewis allograft.


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  		Third-Party Heart Transplants

 

   Comment
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
References
 
In this study we have demonstrated that cardiac allografts transplanted from Lewis to ACI rats survive indefinitely after an immunosuppressive regimen consisting of intravenous injections of a peptide derived from the human MHC class I molecule HLA-B7 (Allotrap 07) given together with CsA. This peptide contains a sequence that is highly homologous to the RT1a MHC sequence present in the ACI recipients (Table 3). Tolerance was donor-specific and did not occur when CsA was omitted from the regimen. These results confirm and extend previous studies using the same peptide, encompassing residues 75-84 of HLA-B7, in which survival of cardiac allografts transplanted into either ACI or LEW.1A recipients, both sharing the RT1a MHC type, was significantly prolonged [11][12]. In contrast, peptides derived from other human HLA-B locus alleles that encode different structures from that present in RT1a-positive rats, such as HLA-B27-02 or HLA-B27-05, are not able to prolong allograft survival [11][12].


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  		Comparison of the Sequence of Allotrap (HLA-B7, Residues 75-84) and Rata RT1 (Residues 75-84)1

 
The alpha-helical region of the HLA-B molecule heavy chain comprising residues 75-84 contains a supratypic serologic epitope present on all HLA-B alleles, which is recognized by alloantisera as either Bw4 or Bw6. Any given HLA-B allele expresses either epitope in mutual exclusion. The residues involved in forming these determinants map to positions 77, 80, 81, 82, and 83 of the class I molecule [13][14], and have recently been implicated in functional interactions between MHC class I-bearing cells and natural killer (NK) cells. Targets transfected with HLA-B alleles containing the Bw4 epitope are not lysed by CD3-negative NK cells bearing the NKB1 cellular receptor [14], suggesting that the Bw4 structure is an inhibitory receptor for NKB1 cells. Similarly, the Bw6 structure prevents NK cell-mediated cytolysis by binding to the CD94 receptor on NK cells [15]. Further, particular residues at positions 77 and 80 of HLA-C molecules inhibit NK-mediated cell lysis by binding to yet a third receptor on NK cells [16]. Together, these observations suggest that polymorphic residues within MHC class I molecules act as specific receptors for various populations of NK cells, and that their function may be to enable NK cells to discriminate between autologous cells and foreign cells, the latter being susceptible to spontaneous lysis by virtue of lack of expression of NK-binding structures.

In addition to inhibiting NK cell functions, structures encoded by polymorphic residues within the alpha-1 helical region of the MHC class I molecule also inhibit T-cell receptor (TCR)-induced functions of T lymphocytes. The Bw6 epitope of HLA-B molecules, as well as certain structures in HLA-C molecules, inhibit TCR-mediated target cell lysis or cytokine production [17] by binding to their respective ligands on T-cells, whereas the Bw4 epitope has been shown to inhibit T lymphocyte cytotoxicity directed against targets expressing superantigens [18]. In this regard, Cuturi and associates [11] demonstrated that lymphocytes obtained from the allografts of LEW-1A rats treated with peptide 75-84 from HLA-B7 had significantly lower levels of cytotoxic activity directed to both NK targets and alloantigens. Moreover, there was a significant reduction in the number of allograft-infiltrative T-cells bearing alpha-beta TCR after treatment with the HLA-B7–derived peptide [11]. Because HLA-B7 contains the Bw6 epitope, this suggests that the effects of the B7-derived peptide may have been mediated by direct interactions with CD94 receptors expressed on both NK cells and T lymphocytes.

Major histocompatibility complex class I molecules bind peptides in an allele-specific manner, with selectivity being conferred by polymorphic residues within the peptide-binding groove. Residues 77, 80, and 81 within the Bw4/Bw6 region face into the peptide-binding groove and are predicted to interact directly with bound peptides. In addition, residues 75, 79, and 83 are at the surface of the alpha-helix, and are predicted to interact directly with TCR variable region structures. Substitutions at these residues, particularly in conjunction with those at peptide-binding sites, would be expected to have profound effects on TCR recognition of the MHC+ peptide complex. At residues 75, 79, and 83, the B7-derived peptide contains arg, arg, gly, in common with the RT1a allele present in LEW.1A and ACI rats, whereas the B27-derived peptides (-02 and -05) contain arg, arg, arg, making the latter significantly more positively charged. At positions 77, 80, and 81, however, RT1a differs significantly from HLA-B7, having the same residues as HLA-B27-05, namely asp, thr, leu, which in part encode the Bw4 specificity. Because neither peptide 75-84 derived from HLA-B27-05 [11] nor peptide 75-84 derived from the RT1a molecule itself (C. Cuturi, personal communication) prolonged allograft survival in RT1a recipients, the tolerogenic effect mediated by the HLA-B7 peptide is likely to depend primarily on critical residues that interact directly with both TCR structures present in ACI recipients and CD94 receptors expressed by the alloreactive T-cells.

The role of MHC molecules in modifying alloimmune responses has been supported by both clinical and experimental observations, and this effect appears to be dependent on coadministration of CsA or other immunosuppressive agents. In human studies, multiple blood transfusions have been shown to prolong survival after renal transplantation [19]. In a rat allograft model, whole blood transfusions, as well as extracted donor antigen administration before transplantation, were able to prolong the survival of a subsequent renal transplant only when used in conjunction with CsA [20]. Moreover, Foster and colleagues [21] showed that whereas membrane-bound class I MHC molecules could induce donor-specific unresponsiveness to subsequent rat renal allografts, water-soluble class I MHC molecules could only induce tolerance when combined with subtherapeutic doses of CsA. Similarly, Goto and coworkers [22] showed that prolonged rat cardiac allograft survival could only be achieved by concurrent administration of KCl-extracted soluble donor antigen and CsA immunosuppression.

In our studies, use of the B7-derived peptide alone did not prolong allograft survival. In contrast, treatment with the same peptide in conjunction with CsA resulted in indefinite graft survival. These results are consistent with recent observations in vitro demonstrating that partial activation of TCR by peptides with alterations in TCR contact residues, and that cannot induce clonal proliferation or cytokine production, leads to profound T-cell unresponsiveness on subsequent stimulation with the original immunogenic peptide [23]. In our model, concomitant binding of the peptide to the TCR and to CD94 would send a stimulatory signal to the T-cell, whereas simultaneous treatment with CsA would prevent interleukin-2 production and clonal expansion. The outcome would be anergy to all antigens presented by self-MHC at the time of treatment, including alloantigens. The specificity of this response would be constrained to antigens present at the time, and would not include antigens presented by self-MHC after cessation of treatment. This explains the rapid rejection we observed when a third-party Brown-Norway graft was implanted into RT1a recipients containing Lewis hearts, long after cessation of the treatment protocol.

In the study by Nisco and associates [12], alloantigen-specific anergy induced by treatment with the B7-derived peptide was accompanied by a decreased frequency of allospecific CTL precursors. Zavazava and colleagues [24], however, reported that treatment with soluble HLA class I molecules could not inhibit alloreactive CTL during the first 5 days of allostimulation, a period when the CTL response is mostly polyclonal. Moreover, Parham and coworkers [25] showed that HLA-derived peptides are unable to inhibit polyclonal CTL directed against the HLA molecules from which the peptide is derived. These observations suggest that during the first 5 days of an alloimmune response, the polyclonal T-cell response may overcome the immunosuppressive effects of MHC class I-derived peptides. This may explain why a short course of Allotrap 07 after transplantation failed to induce tolerance in our study, whereas treatment until day 12 was successful. Therefore, the optimal effect of soluble MHC class I-derived peptides on tolerance to the allograft and prolonged survival is likely to require peptide administration for more than 6 to 10 days after transplantation.

In contrast to intravenous administration of the peptide, which resulted in tolerance induction in 7 of 8 ACI recipients, intraperitoneal delivery was only associated with induction of tolerance in 3 of 8 recipients. This may reflect differences in peptide kinetics when administered by intravenous and intraperitoneal routes. Intraperitoneal administration of Allotrap is likely to be associated with slower absorption and lower initial blood levels than intravenous administration, thus potentially decreasing the efficacy of the peptide during initial allograft exposure. Additionally, intraperitoneal administration may be associated with a half-life of circulating Allotrap peptide that is significantly longer than the 2 to 3 minutes after intravenous administration. More prolonged exposure to circulating Allotrap could result in loss of the tolerogenic properties of the peptide, with some T-cell clones being activated, rather than inhibited, after prolonged TCR ligation. In support of such a mechanism, Faugmann and associates [26] have shown that synthetic peptides corresponding to residues 57-80 of the RT1a molecules were immunogenic rather than tolerogenic when administered in complete Freund’s adjuvant. In future studies we anticipate further evaluation of the dynamics of T-cell–MHC interactions and the pharmacokinetics of the HLA-derived peptides. More interestingly, the success of human class I-derived peptide in rodent allotransplantation encourages the possibility of developing a single agent for tolerance induction in human transplantation.


   References
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 References
 

  1. Penn I Cancers following cyclosporine therapy. Transplantation 1987;43:32-35.[Medline]
  2. Mihatsch MJ, Thiel G, Ryffel B Cyclosporine nephrotoxicity. Adv Nephrol 1988;17:303-320.
  3. Kim JH, Perfect JR Infection and cyclosporine. Rev Infect Dis 1989;2:677-690.
  4. Salaman JR, Griffin PJA Immunosuppression with a combination of cyclosporine, azathioprine and prednisolone may be unsafe. Lancet 1985;2:1066-1067.
  5. Schneck J, Maloy WL, Coligan JE, Margaulies DH Inhibition of an allospecific T cell hybridoma by soluble class I proteins and peptides: estimation of the affinity of a T cell receptor for MHC. Cell 1989;56:47-55.[Medline]
  6. Clayberger C, Parham P, Rothbard J, et al. HLA-A2 peptides can regulate cytolysis by human allogeneic T lymphocytes. Nature 1987;330:763-765.[Medline]
  7. Arnold B, Messerle M, Jatsch L, Kublbeck G, Koszinowski U Transgenic mice expressing a soluble foreign H-2 class I antigen are tolerant to allogeneic fragments presented by self class I but not to the whole membrane bound alloantigen. Proc Natl Acad Sci USA 1990;87:1762-1766.[Abstract/Free Full Text]
  8. Zemmour J, Parham P HLA class I nucleotide sequences. Immunogenetics 1991;33:310-320.[Medline]
  9. Clayberger C, Lyn S-C, Pouletty P, Krensky AM Peptides corresponding to T cell receptor-HLA contact regions inhibit class I restricted immune responses. Transplant Proc 1993;25:477-478.[Medline]
  10. Ono K, Lindsey ES Improved technique of heart transplantation in rats. J Thorac Cardiovasc Surg 1969;57:225-229.[Medline]
  11. Cuturi MC, Josien R, Cantarovich D, et al. Prolongation of allogeneic heart graft survival in rats by administration of a peptide (a.a. 75-84) from the alpha-1 helix of the first domain of HLA-B7-01. Transplantation 1995;59:661-669.[Medline]
  12. Nisco S, Vriens P, Hoyt G, et al. Induction of allograft tolerance in rats by an HLA class I-derived peptide and cyclosporine A. J Immunol 1994;152:3786-3792.[Abstract]
  13. Muller CA, Engler-Blum G, Gekeler V, Steiert I, Weiss E, Schmidt H Genetic and serological heterogeneity of the supertypic HLA-B locus specificities Bw4 and Bw6. Immunogenetics 1989;30:200-207.[Medline]
  14. Gumperz JE, Litwin V, Phillips JH, Lanier LL, Parham P The Bw4 public epitope of HLA-B molecules confers reactivity with natural killer cell clones that express NKB1, a putative HLA receptor. J Exp Med 1995;181:1133-1144.[Abstract/Free Full Text]
  15. Moretta A, Vitale M, Sivori S, et al. Human NK cell receptors for HLA-class I molecules. Evidence that the Kp43 (CD94) molecule functions as receptor for HLA-B alleles. J Exp Med 1994;180:545-555.[Abstract/Free Full Text]
  16. Moretta A, Vitale M, Bottino C, et al. P58 molecules as putative receptors for MHC class I molecules in human NK cells. Anti-P58 antibodies reconstitute lysis of MHC class-protected cells in NK clones displaying different specificities. J Exp Med 1993;178:597-604.[Abstract/Free Full Text]
  17. Mingari CM, Vitale C, Cambiaggi A, et al. Cytolytic T lymphocytes displaying natural killer (NK)-like activity: expression of NK-related functional receptors for HLA class I molecules (p58 and CD94) and inhibitory effect on the TCR-mediated target cell lysis or lymphokine production. Int Immunol 1995;7:697-703.[Abstract/Free Full Text]
  18. Phillips JH, Gumperz JE, Parham P, Lanier LL Superantigen-dependent, cell-mediated cytotoxicity inhibited by MHC class I receptors on T lymphocytes. Science 1995;268:403-405.[Abstract/Free Full Text]
  19. Opelz G, Terasaki PL Improvement of kidney graft survival with increased numbers of blood transfusions. N Engl J Med 1978;299:799-803.[Abstract]
  20. Kahan BD, Yasamura T Prolongation of rat kidney allografts by pretransplant administration of donor antigen extract or whole blood transfusion combined with short course of cyclosporine. Transplantation 1983;36:603-609.[Medline]
  21. Foster S, Wood KJ, Morris PJ The effectiveness of pretreatment with soluble or membrane bound donor class I MHC antigens in the induction of unresponsiveness to a subsequent rat renal allograft. Transplantation 1992;53:1322-1328.[Medline]
  22. Goto S, Stepkowski SM, Kahan BD Multiple injections of KCL-extracted donor-antigen in combination with a short course of cyclosporine therapy induces prolonged heart allograt survival in rats. Transplant Proc 1989;21:3300-3302.[Medline]
  23. Sloan-Lancaster J, Evavold BD, Allen PM Induction of T-cell anergy by altered T-cell receptor ligand on live antigen-presenting cells. Nature 1993;363:156-159.[Medline]
  24. Zavazava N, Hausmann R, Muller-Ruchholtz W Inhibition of anti-HLA-B7 alloreactive CTL by affinity-purified soluble HLA. Transplantation 1991;51:838-842.[Medline]
  25. Parham P, Clayberger C, Zorn SL, Ludwig DS, Schoolnik GK, Kresky AM Inhibition of alloreactive cytotoxic T lymphocytes by peptides from the alpha-2 domain of HLA-A2. Nature 1987;325:625-628.[Medline]
  26. Faugmann J, Dalchau R, Fabre JW Rejection of skin allografts by indirect allorecognition of donor class I MHC peptides. Transplant Proc 1993;25:183-184.[Medline]



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