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(Circulation. 1995;92:82-87.)
© 1995 American Heart Association, Inc.

Articles

Cardiac Allograft Survival in Mice Deficient in Intercellular Adhesion Molecule–1

Kenneth O. Schowengerdt, MD; Jessica Y. Zhu, MD; Stanislaw M. Stepkowski, PhD; Yizheng Tu, MD; Mark L. Entman, MD; Christie M. Ballantyne, MD

From the Departments of Pediatrics (K.O.S., C.M.B.) and Medicine (J.Y.Z., M.L.E., C.M.B.), Baylor College of Medicine, and the Department of Surgery (S.M.S., Y.T.), University of Texas Health Science Center, Houston.

Correspondence to Christie M. Ballantyne, MD, Department of Internal Medicine, MS A601, 6565 Fannin St, Houston, TX 77030.

	Abstract

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Background Intercellular adhesion molecule–1 (ICAM-1, CD54) is a cell adhesion molecule that interacts with the leukocyte ß2 integrins, lymphocyte function–associated antigen–1, and macrophage antigen–1. ICAM-1 is postulated to play a key role in several cell-cell interactions that are important in allograft rejection, including antigen presentation, transendothelial migration of leukocytes, and leukocyte-mediated myocyte injury.

Methods and Results Mice homozygous for a gene-targeted mutation of ICAM-1 were used in two different cardiac transplant models to further define the role of ICAM-1 in the process of allograft rejection. In the first model, hearts from newborn mice were implanted in the ear pinnae of H-2–incompatible recipients. In the second model, intra-abdominal transplantation by direct vascular anastomosis was performed. Time to rejection was defined by the loss of pulsatile activity assessed by visual inspection in the ear model or by cessation of palpable cardiac impulse in the abdominal model. Allograft survival did not differ significantly between control groups that express normal levels of ICAM-1 and those groups using ICAM-1–deficient mutants as either donors or recipients. Histological examination of rejection of both normal and mutant (ICAM-1-deficient) cardiac allografts revealed similar patterns of infiltration of mononuclear and granulocytic leukocytes and myocyte necrosis. Immunostaining with anti–ICAM-1 antibodies showed ICAM-1–positive infiltrating cells in both mutant (ICAM-1–deficient) and normal allografts, with the graft endothelium negative for ICAM-1 staining in the mutant allografts.

Conclusions The absence of surface expression of ICAM-1 in the donor allograft or recipient is insufficient to produce a significant impact on cardiac allograft survival. This study highlights the need to understand more precisely the mechanism of action whereby monoclonal antibodies to ICAM-1 prolong cardiac allograft survival before new therapeutic strategies based on gene transfer technology or small molecule inhibitors are developed. Mutant mice with targeted mutations in cell adhesion molecules provide powerful tools to study the complex role that cell adhesion molecules play in the cellular interactions between donor graft tissue and the recipient that culminate in graft rejection.

Key Words: leukocytes • cell adhesion molecules • rejection

	Introduction

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Heart transplantation has evolved from an experimental procedure to the treatment of choice for many patients with end-stage congestive heart failure. However, both acute and chronic rejection and the complications of nonspecific immunosuppressive therapy remain limiting factors to recipient survival. Recent advances in the study of the molecular basis of inflammation suggest that cell-cell interactions mediated by specific adhesion molecules could be new targets for immunosuppressive therapy. Cell adhesion molecules are postulated to play an important role in three key steps of allograft rejection: (1) the initial alloantigen recognition leading to T-cell activation, (2) subsequent migration of leukocytes from the intravascular space into tissue, and (3) leukocyte-mediated myocyte injury.^{1 2} Interaction between the T-cell receptor and peptides bound to major histocompatibility complex (MHC) class I or II molecules is felt to require adhesive strengthening with additional interaction between these cell adhesion molecules.

Intercellular adhesion molecule–1 (ICAM-1, CD54) is a cell adhesion molecule of the immunoglobulin supergene family that interacts with the leukocyte ß2 integrins: lymphocyte function–associated antigen–1 (LFA-1, CD11a), macrophage antigen–1 (Mac-1, CD11b), and p150,95 (CD11c). The interaction of ICAM-1 and LFA-1 may play an important role in antigen presentation, T-cell activation, and leukocyte extravasation. Optimal T-cell function in vitro is dependent on the interaction of ICAM-1 and LFA-1 as demonstrated by the inhibitory effects of antibodies directed against these proteins on T-cell–mediated lysis,³ T-cell help to B cells,⁴ antigen-induced T-cell mitogenesis,⁵ and mixed lymphocyte response.⁶ In addition, mutant murine cell lines deficient in ICAM-1 expression showed decreased ability to present antigens to T cells. This function was restored by transfection of these cells with the murine ICAM-1 cDNA.⁷ Analysis of human and monkey cardiac allografts by others showed increased ICAM-1 expression during acute rejection.^{8 9 10 11}

Parenteral administration of monoclonal antibodies (MAb) to ICAM-1 or LFA-1 alone prolonged the survival of vascularized murine cardiac allografts; when administered in combination, these antibodies induced donor-specific transplantation tolerance.¹² Prophylactic administration of MAb to ICAM-1 for 2 days before transplantation and 10 days after transplantation has been shown to prolong cardiac allograft survival in a primate study.⁹ In addition, in a phase I clinical trial, administration of anti–ICAM-1 to human renal transplant recipients at high risk for delayed graft function has shown encouraging results.¹³

The present experiments were performed with mutant mice developed at our institution that were rendered deficient in ICAM-1 expression by gene targeting with homologous recombination in embryonic stem cells.¹⁴ In homozygous adult mutant mice that have a targeted disruption in exon 5, immunohistochemical staining of the lung, an organ known to express significant amounts of ICAM-1 in the mouse, showed a loss of surface expression of ICAM-1. In addition, RNA analysis of these animals by reverse transcription–polymerase chain reaction and Northern blot analysis confirmed loss of expression of ICAM-1. Mice deficient in ICAM-1 exhibited a 74% suppression of contact hypersensitivity, and lymphocytes from mutant mice provided negligible stimulation in the mixed lymphocyte reaction, although they proliferated normally as responder cells. ICAM-1–deficient mice also showed impaired migration of neutrophils in response to chemical peritonitis.¹⁴ Using this information and previous studies by others, we hypothesized that the use of cardiac allografts lacking surface expression of ICAM-1 might lead to prolongation of graft survival. In this study, we performed experiments to examine whether a deficiency of ICAM-1 in either the allograft or the recipient would lead to an alteration in allograft survival or would markedly alter the pattern of leukocytic extravasation into the graft.

	Methods

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Animals
The AB-1 embryonic stem cell line derived from 129Sv (H-2^b) mice was used for targeted homologous recombination with subsequent injection of clones into C57BL/6J (H-2^b) females.¹⁴ Chimeric males were mated with C57BL/6J (H-2^b) females. Heterozygous offspring were backcrossed to develop mice homozygous for the targeted mutation of ICAM-1. Wild-type 129Sv littermates that expressed normal levels of ICAM-1 were bred with C57BL/6J mice to serve as 129SvxC57BL/6J controls. CBA (H-2^k) mice were used as the H-2-incompatible recipients or donors.

Transplantation Models
Two models of heterotopic cardiac allograft rejection were used. In the first model, hearts from newborn mice were implanted in the ear pinnae of 12- to 24-week-old H-2–incompatible recipients by use of the method of Judd and Trentin.¹⁵ ICAM-1–deficient mutants (129SvxC57BL/6J) were used as either donors or recipients. Control groups consisted of transplantations between CBA mice and wild-type 129SvxC57BL/6J mice (normal levels of ICAM-1) used as either donors or recipients. Time to rejection, measured in days, was defined by the absence of cardiac contractility as assessed daily by direct visualization under x10 magnification. In the second transplantation model, one involving primary vascularization, abdominal heterotopic transplantation was performed in H-2–incompatible recipients by the modified method of Corry et al.¹⁶ In this model, ICAM-1–deficient mutant mice were again used as donors or recipients, and direct vascular anastomosis of the graft was performed (donor pulmonary artery to recipient inferior vena cava; donor aorta to recipient abdominal aorta). In the control group, hearts from the wild-type (129SvxC57BL/6J) mice were transplanted into CBA recipients. Cardiac function was evaluated by daily abdominal palpation, and the day of cardiac impulse cessation was considered the day of rejection.

Immunohistochemistry
For immunohistochemical staining studies, abdominal heterotopic transplantations were performed in a second group of animals. ICAM-1–deficient donor hearts were transplanted into H-2–incompatible wild-type recipients, and the transplanted hearts were harvested at multiple time points (days 6 through 14) after transplantation, which corresponded to the time frame preceding the loss of pulsatile activity to several days after loss of pulsation. Similar transplantations were performed with wild-type donor hearts (normal levels of ICAM-1) for comparison, and the hearts were harvested at the same time period after transplantation. Cardiac tissue was fixed in 4% paraformaldehyde immediately after harvesting for 4 hours. The tissue was then embedded in paraffin, and 4-µm-thick tissue sections were prepared. Sections were stained with hematoxylin and eosin for conventional histological evaluation. In addition, immunohistochemical staining for ICAM-1 and granulocytes was carried out with the rat monoclonal antibodies YN1 and GR1, respectively. For staining, sections were blocked with 5% rat serum, washed in PBS, and treated with primary antibody overnight at 4°C. The rat monoclonal antibody YN1 (American Type Culture Collection) is specific for murine ICAM-1; the rat monoclonal GR1 (Pharmingen) is specific for granulocytes. Each antibody was titered for optimal reactivity. After washing in PBS, the bound primary antibody was detected by use of the Vectastain ABC Elite kit (Vector Laboratories) with DAB as the chromagen. Sections were then counterstained with eosin.

	Results

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Neovascularized Cardiac Transplantation
Neovascularized heart grafts were performed by transplantation of newborn murine hearts into a subcutaneous pocket created in the ear pinnae of recipients. Rejection was determined by direct visualization of loss of graft pulsation. Four experimental groups were examined. The first two groups were done to compare homozygous ICAM-1–deficient (129SvxC57BL/6J) mice (n=17) and wild-type (129SvxC57BL/6J) mice (n=9) used as donors with H-2–disparate CBA mice as recipients. Conversely, CBA cardiac allografts were grafted into homozygous ICAM-1–deficient (n=12) and ICAM-1–normal wild-type recipients (n=5). In all groups examined, cardiac allografts were rejected with a mean survival time (MST) of approximately 10 days, with individual graft survival ranging from 9 to 12 days (Fig 1). No significant differences were noted (using the Kruskal-Wallis test) between groups using the ICAM-1–deficient mutant mice as either donors or recipients and the wild-type control groups.

View larger version (21K): [in this window] [in a new window]   Figure 1. Graph showing time to rejection of cardiac allografts in a neovascularized model using intercellular adhesion molecule–1 (ICAM-1)–deficient mutants as donors or recipients determined by loss of cardiac contractility assessed by direct visualization.

Vascularized Cardiac Transplantation
Because the process of neovascularization that occurs in the ear model could in theory affect the ICAM-1–dependent processes of antigen presentation and graft infiltration by leukocytes, similar experiments were performed using a primary vascularization model involving heterotopic abdominal cardiac transplantation. Graft survival with this model was determined by noting the absence of graft pulsation by daily abdominal palpation. ICAM-1–deficient (129SvxC57BL/6J) cardiac allografts were rejected with an MST of 7.5 days by CBA recipients (n=10). Similarly, CBA recipients rejected control wild-type (129SvxC57BL/6J) hearts with an MST of 7.3 days (n=4). In reverse donor-recipient combination, ICAM-1–deficient recipients rejected CBA cardiac allografts with an MST of 8.4 days, with individual graft survival ranging from 6 to 12 days (n=10). Differences between groups with this model were not statistically significant (the Kruskal-Wallis test). Results are expressed graphically in Fig 2.

View larger version (18K): [in this window] [in a new window]   Figure 2. Graph showing time to rejection of cardiac allografts in a primarily vascularized model using intercellular adhesion molecule–1 (ICAM-1)–deficient mutants as donors or recipients determined by loss of cardiac contractility assessed by palpation.

Histological Examination of Cardiac Allografts
To confirm that expression of ICAM-1 in the heart could be induced in the wild-type mice but not in the mutants, immunohistochemical staining was performed on cardiac tissue from wild-type and mutant mice 24 hours after administration of 50 µg IP of lipopolysaccharide. Areas of intense endothelial staining were noted in the wild-type mouse after administration of lipopolysaccharide, whereas staining of cardiac tissue from the stimulated mutant mouse confirmed the absence of surface expression of ICAM-1 (Fig 3). Immunohistochemical staining for ICAM-1 and granulocytes was examined at several time points in murine donor allografts undergoing rejection obtained from both normal and mutant animals (primary vascularization model). Endothelial staining for ICAM-1 is noted in the donor allograft obtained from the normal mouse that was harvested on day 6 after transplantation (Fig 4). In contrast, the donor allograft obtained from a mutant mouse is devoid of ICAM-1 staining at this time point, which precedes significant rejection (Fig 4). Staining with GR1 for granulocytes revealed the presence of extravascular granulocytes in allografts from both normal and mutant donors, although the number of granulocytes appeared to be mildly reduced in the mutant mice (Fig 4). At later time points (day 9 and later), intense leukocytic infiltration with prominent myocyte necrosis was noted in allografts from both mutant and wild-type mice. By day 9, substantial ICAM-1 staining was noted in the allografts derived from mutant hearts. However, this staining emanated from infiltrating mononuclear cells positive for ICAM-1 that were adherent to the endothelium, below the endothelium, and in the perivascular space (Fig 5).

View larger version (0K): [in this window] [in a new window]   Figure 3. Photomicrographs showing cardiac tissue harvested 24 hours after administration of lipopolysaccharide 50 µg IP and stained for intercellular adhesion molecule–1 (ICAM-1) using the monoclonal antibody YN1. Top, No staining is observed in cardiac tissue from the ICAM-1–deficient mutant mouse. Bottom, Intense endothelial staining is observed in this section of cardiac tissue taken from a wild-type control mouse. Magnification x350.

View larger version (0K): [in this window] [in a new window]   Figure 4. Top, Photomicrographs showing cardiac allografts (abdominal heterotopic) harvested at day 6 and stained for intercellular adhesion molecule–1 (ICAM-1) with the monoclonal antibody YN1. Top left, ICAM-1–deficient mutant allograft; wild-type CBA recipient. No endothelial staining is seen. Top right, ICAM-1–normal allograft; wild-type CBA recipient. Multiple areas of endothelial staining are noted. Magnification x250. Bottom, Photomicrographs showing cardiac allografts (abdominal heterotopic) harvested at day 7 and stained for granulocytes with the monoclonal antibody GR-1. Bottom left, ICAM-1–deficient mutant allograft; normal CBA recipient. Bottom right, ICAM-1–normal allograft; normal CBA recipient. Infiltrating granulocytes are observed in both the mutant and wild-type allografts. Magnification x350.

View larger version (0K): [in this window] [in a new window]   Figure 5. Photomicrographs showing intercellular adhesion molecule–1 (ICAM-1)–deficient cardiac allografts (abdominal heterotopic) harvested at day 9 and stained for ICAM-1. Infiltrating cells that stain for ICAM-1 are present. Magnification: top, x350; bottom, x175.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
Monoclonal antibodies directed against ICAM-1 have been shown by others to prolong cardiac allograft survival in several animal models.^{9 12} Cell adhesion molecules may play a critical role in several different steps in the immune-mediated response to destroy a foreign allograft. However, the exact mechanism for the protective effects of the MAb to ICAM-1 in the delay of allograft rejection is unknown. The initial hypothesis of this study was that allografts from ICAM-1–deficient mice would have prolonged survival because they would have defects in antigen presentation, transendothelial migration of leukocytes, and neutrophil-mediated myocyte injury. Initial experiments showed that mutant mice deficient in ICAM-1 show no prolongation of graft survival when used as donors or recipients in a model of heterotopic cardiac allograft transplantation in the pinna of the ear. Because the process of neovascularization could theoretically affect both antigen presentation and the process of leukocyte extravasation, a second model of heterotopic cardiac allograft transplantation was performed with direct vascularization. In this model, mutant mice deficient in ICAM-1 once again failed to show any prolongation of graft survival when used as donors or recipients. Histological data confirmed extravasation of both mononuclear cells and granulocytes, along with myocyte necrosis in the revascularized allografts in a pattern similar to that of wild-type allografts, despite the absence of ICAM-1 on the endothelium.

Lymphocytes from ICAM-1–deficient mice are poor stimulators in the mixed lymphocyte reaction but function normally as responder cells. This observation and previous in vitro data supported our initial hypothesis that ICAM-1–deficient cardiac allografts would have impaired antigen presentation and therefore prolonged graft survival. Our results clearly do not support this hypothesis. There are several possibilities to explain how antigen presentation could proceed normally, even with the lack of ICAM-1 in the cardiac allograft.

The predominant theories on the mechanism of graft rejection are based on the capacity of T cells to directly recognize allogeneic MHC antigens without the requirement that peptides be processed by recipient antigen presenting cells. The "direct response" would involve either a CD4+ direct response to allogeneic class II antigens or a CD8+ direct response to class I antigens. Recent studies in MHC class II–deficient mice suggested graft rejection is dependent on an "indirect response" in which peptides of donor antigens are processed by recipient cells and presented in association with recipient MHC molecules.¹⁷ If this is the case, the recipient monocytes that express normal amounts of ICAM-1 may be processing the donor peptides and functioning as antigen presenting cells. As noted in Fig 5, infiltrating mononuclear cells were clearly positive for ICAM-1. The role of "indirect" recognition has important implications for the development of gene transfer technology in transplantation. As a consequence of the process of indirect recognition, strategies that inhibit the expression of molecules involved in antigen expression by the graft may be unsuccessful. Treatment with monoclonal antibodies would block both direct and indirect antigen presentation. ICAM-1–deficient mice of different H-2 backgrounds are currently being bred to examine whether a deficiency of ICAM-1 in both donor and recipient might lead to graft prolongation.

A second potential explanation for the normal antigen presentation may be the redundancy of cell adhesion molecules, which can strengthen the adhesive interaction between the T-cell receptor and the MHC complex. Previous studies in the mouse showed that antibodies to ICAM-1 alone have only a modest effect on prolongation of graft survival, which is greatly enhanced by additional therapy with an antibody to LFA-1.¹² ICAM-2 and ICAM-3 can also serve as ligands for LFA-1. In addition, very late antigen–4 (VLA-4) and vascular cell adhesion molecule–1 (VCAM-1) may play a role in antigen presentation. VLA-4 has been shown to have some involvement in T-cell–mediated killing¹⁸ and in homotypic adhesion,¹⁹ which suggests some functional redundancy with LFA-1. Antibodies to VLA-4 and LFA-1 were able to inhibit >50% of the binding of lymphocytes to rejecting cardiac allografts in an ex vivo assay.²⁰ Monoclonal antibodies to VCAM-1 were shown by others to induce long-term survival in a vascularized model of murine heart transplantation.²¹ Treatment with a monoclonal antibody to VLA-4 was shown to modestly reduce histological evidence of vascular rejection with no benefit on cellular rejection in a rabbit model of heterotopic heart transplantation²² and to prolong cardiac allograft survival in a vascularized rat model.²³

A third mechanism to explain our results would be the upregulation of other pathways for leukocyte recruitment owing to the chronic lack of ICAM-1 throughout embryogenesis and development. However, no differences were found for wild-type and mutant animals for populations of CD11a+, ICAM-2+, CD3+, CD45R+, CD4+, and CD8+ cells in the spleen, nor were differences found for thymic T-cell subsets of CD4+ CD8-, CD4- CD8+, or CD4+CD8+ cells.¹⁴

The data from these studies suggest that inhibition of leukocyte transendothelial migration and neutrophil-mediated myocyte injury are not the major mechanisms of benefit with MAb treatment. The absence of ICAM-1 in the heart is insufficient to prevent extravasation of leukocytes or myocyte injury and necrosis. The majority of infiltrating leukocytes are mononuclear lymphocytes and monocytes with fewer neutrophils. ICAM-1 has previously been shown to be involved only in neutrophil-mediated myocyte injury, and the cell adhesion molecules in mononuclear cell–mediated myocyte injury are not known. Other cell adhesion molecules such as VLA-4 and VCAM-1 may be important in the role of mononuclear cell transmigration during allograft rejection. VLA-4 is present on both lymphocytes and monocytes, and VCAM-1 expression is induced on the endothelium during allograft rejection.²⁴ The relatively normal extravasation of mononuclear cells might have been predicted from clinical studies of patients with the human genetic disorder leukocyte adhesion deficiency. These patients have a mutation of the ß2 integrin CD18, with a resultant deficiency of LFA-1, Mac-1, and p150,95. These patients have seriously impaired migration of granulocytes more than lymphocytes.²⁵

The results of this study highlight the need to understand more fully the precise mechanism of the protective effect of MAb directed against cell adhesion molecules before other therapeutic modalities such as gene therapy or small molecule inhibitors are developed. Some mutant mice with targeted mutations for several cell adhesion molecules have been developed, and others are being developed. These mice will provide powerful tools to dissect the complex role that cell adhesion molecules play in the cellular interactions between donor graft tissue and the recipient that culminate in graft rejection.

	Acknowledgments

 
This work was supported in part by NHLBI grants F32-HL-08611-01 (Dr Schowengerdt), HL-02537 (Dr Ballantyne), and HL-42550 (Drs Ballantyne and Entman); the American Heart Association, National Sanofi Winthrop Awardee and Texas Affiliate, Inc (Dr Ballantyne); and a Caroline Wiess Law Grant for Molecular Medicine (Dr Ballantyne). We gratefully acknowledge expert technical assistance from Elizabeth Priest, advice from John Trentin, PhD, and manuscript preparation by Rima Farhat.

	Footnotes

 
Guest editor for this article was J. David Bristow, MD, Oregon Health Sciences University, Portland.

Received August 1, 1994; revision received December 15, 1994; accepted January 2, 1995.

	References

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