Biomedical subjects

T Mohanakumar

Publications and source records attributed to T Mohanakumar.

At least 19 recordsLinked to original sources

PubMed2006

A significant role for histocompatibility in human islet transplantation.

BACKGROUND: In recent years, transplantation of islets and pancreas has become a viable option for patients debilitated with type I diabetes. The success of islet transplantation has been attributed to the ability to isolate high quality islets for transplantation and capacity to maintain the recipient's immunosuppressive levels within a specific target range following transplantation. The purpose of this study was to determine the role of pretransplant sensitization to human leukocyte antigen (HLA) in islet transplantation. METHODS: We retrospectively analyzed seven patients that were transplanted with islets under the auspices of the Juvenile Diabetes Research Foundation and Islet Cell Resource Center/National Institutes of Health. Humoral sensitization towards donor antigens both prior to and following islet transplantation was detected by FLOW panel reactive antibodies (PRA) and donor-specific cellular sensitization was detected by performing enzyme-linked immunospot assay analysis for cytokines interferon-gamma and interleukin-2. RESULTS: Our analysis demonstrates that humoral and cellular sensitization to histocompatibility antigens prior to and after islet transplantation are associated with the failure of transplanted islets CONCLUSION: Patient selection based on sensitization to donor HLA may be one of the factors crucial for the success of islet transplant. Further, in some patients, rejection of islets can be associated with sensitization to mismatched donor histocompatibility antigens.

Diabetes Mellitus, Type 1↗

PubMed2006

Role of airway epithelial injury in murine orthotopic tracheal allograft rejection.

BACKGROUND: Murine tracheal transplantation is a model used to study bronchiolitis obliterans syndrome, a major cause of morbidity and mortality after lung transplantation. Unlike murine heterotopic tracheal transplants, orthotopic transplantation does not cause luminal obliteration despite major histocompatibility antigen mismatch. Repopulation of the tracheal allografts with recipient-derived epithelium confers protection against luminal obliteration. The purpose of this study was to determine whether (1) orthotopic tracheal transplantation showed signs of allograft rejection, and (2) airway epithelial cell injury promoted orthotopic tracheal allograft rejection. METHODS: Forty isogeneic (C57BL/6 to C57BL/6) and 40 allogeneic (BALB/c to C57BL/6) orthotopic tracheal transplants were performed. Damage to airway epithelial cells was induced by Sendai viral (SdV) infection and tracheal transplantation into non-reepithelializing matrix metalloproteinase-7 knockout (MMP7-KO) recipient mice. Percent fibrosis and lamina propria to cartilage ratio were calculated with computer assistance on harvested allografts. RESULTS: Allografts showed significantly more intramural fibrosis compared with isografts at 30, 60, and 180 days after transplant without luminal occlusion. Tracheal allografts infected with SdV showed an increase in fibrosis and lamina propria to cartilage ratio compared with noninfected controls. Allografts retrieved from MMP7-KO recipients also showed a significant increase in fibrosis and lamina propria to cartilage ratio. CONCLUSIONS: Although orthotopic tracheal transplantation does not cause luminal obliteration, it results in increased fibrosis in allografts. Damage to the respiratory epithelium by viral infection or defective reepithelialization after transplant as seen in MMP7-KO recipient mice leads to changes consistent with chronic allograft rejection, suggesting a role for epithelial injury in bronchiolitis obliterans syndrome development.

Animals↗

PubMed2006

Complement depletion enhances pulmonary inflammatory response after liver injury.

Hepatic cryoablation can produce acute lung injury, with activation of nuclear factor (NF)-kappaB in the remnant liver and lungs, production of C-X-C chemokines, and neutrophil infiltration of the lungs. Activated complement stimulates NF-kappaB and cytokine secretion from Kupffer cells. The role of complement in the development of acute lung injury after cryoablation was examined using HLL transgenic mice (5'HIV-LTR-Luciferase gene; 5' HIV-LTR is an NF-kappaB-dependent promoter). Total complement depletion was achieved with preoperative administration of cobra venom factor (CVF). After hepatic cryoablation, bioluminescent NF-kappaB activity increased in the nonablated liver remnant by 4 hours in both control (119,093 +/- 22,808 net RLU/mg protein) and CVF-treated mice (117,722 +/- 14,932) from cumulative baseline (657 +/- 90, P < 0.0001). In the lung, complement-depletion induced significantly greater increases in NF-kappaB activation at both early and later times. Likewise, chemokines were higher in complement-depleted mice relative to controls (KC: 493 +/- 43 versus 269 +/- 29 pg/mg protein, P < 0.001; MIP-2: 171 +/- 29 versus 64 +/- 13 pg/mg protein, P < 0.0001). Pulmonary myeloperoxidase activity was equivalent at 24 hours, but complement-depletion caused a significantly more rapid influx of neutrophils. Complement depletion results in increased pulmonary inflammation following liver cryo injury via relative upregulation of NF-kappaB activity. Activated complement is not the initiator of the systemic inflammatory response; in fact, downstream components of the complement cascade may diminish subsequent inflammation.

Analysis of Variance↗

PubMed2006

Survival of long nerve allografts following donor antigen pretreatment: a pilot study.

In this study, the authors evaluated whether the pretransplant portal venous administration of UV-B irradiated donor alloantigen would induce tolerance to long peripheral nerve allografts in a swine model. They completed nerve allograft transplantation between four swine of separate lineages. Regeneration across the nerve allografts was followed for 10 months postoperatively. Sequential IN VITRO assays demonstrated the successful and prolonged suppression of the recipient immune response to donor antigen following antigen inoculation. Histomorphometric analysis demonstrated successful regeneration across the long nerve allografts in the pretreated recipients, but not across allografts in unimmunosuppressed recipients. A single pretransplant antigen delivery protocol has the potential to replace chronic medicinal immunosuppressant therapy and its associated morbidities. Furthermore, tolerance to long nerve allografts has immediate applicability to clinical requirements for bridging multiple, complex, long nerve gaps.

Animals↗

PubMed2006

Improved islet yields from pancreas preserved in perflurocarbon is via inhibition of apoptosis mediated by mitochondrial pathway.

Islet transplantation is a treatment option for type I diabetic patients. Preservation of human pancreata prior to islet isolation using two-layer method with perfluorocarbon (PFC) and University of Wisconsin solution (UW) results in twofold increase in islet yields. The objective of this study was to determine the mechanism by which islets undergo apoptosis and determine PFC's effects on this process. Gene array analysis was used to analyze the expression of pro- and anti-apoptotic genes in islets isolated from pancreata preserved under varying conditions. A 12-fold increase in the expression of inhibitor of apoptosis (IAP) and survivin was observed in islets isolated from pancreata preserved in PFC. This was accompanied by decreased expression of BAD (3.7-fold), BAX (2.7-fold) and caspases (5.2-fold). Levels of activated caspase-9 (77.98%), caspase-2 (61.5%), caspase-3 (68.3%) and caspase-8 (37.2%) were also reduced. 'Rescue' of pancreata after storage (12 h) in UW by preservation using PFC also resulted in a down-regulation of pro-apoptotic genes and inhibition of caspase activation. Apoptosis observed in islets from all groups was mainly mitochondria-dependent, mediated by change in redox potential initiated by hypoxia. We demonstrate that reduction in hypoxia of pancreata preserved using PFC leads to significant up-regulation of anti-apoptotic and inhibition of pro-apoptotic genes.

Apoptosis↗

PubMed2006

CD4+25+ regulatory T cells limit Th1-autoimmunity by inducing IL-10 producing T cells following human lung transplantation.

Chronic human lung allograft rejection is manifested by bronchiolitis obliterans syndrome (BOS). BOS has a multifactorial etiology. Previous studies have indicated that both cellular and humoral alloimmunity play a significant role in the pathogenesis of BOS. Recently, autoimmunity has also been demonstrated to contribute to lung allograft rejection in animal models. However, the significance of autoimmunity in BOS remains unknown. In this report, we investigated the role of naturally occurring CD4(+)CD25(+) regulatory T cells (T-regs) in modulating cellular autoimmunity to collagen type V (col-V), a 'sequestered' yet immunogenic self-protein present in the lung tissue, following lung transplantation (LT). We demonstrated that col-V reactive CD4(+) T cells could be detected in the peripheral blood of lung transplant recipients. There was a predominance of IL-10 producing T cells (T(IL-10)) reactive to col-V with significantly lower levels of IFN-gamma and IL-2 producing T cells (Th1 cells). The col-V specific T(IL-10) cells suppressed the proliferation and expansion of col-V specific Th1 cells by IL-10-dependent and contact-independent pathways. The T(IL-10) cells were distinct but their development was dependent on the presence of T-regs. Furthermore, during chronic lung allograft rejection there was a significant decline of T(IL-10) cells with concomitant expansion of col-V-specific IFN-gammaproducing Th1 cells.

Autoimmunity↗

PubMed2005

HLA class I antibody mediated accommodation of endothelial cells via the activation of PI3K/cAMP dependent PKA pathway.

Allografts transplanted across ABO incompatibility or human leucocyte antigen (HLA)-sensitization undergoes antibody (Ab) mediated hyperacute rejection. Depleting anti-graft Ab from the recipient by plasmapheresis prior to transplantation can prevent this Ab-mediated rejection. Under these conditions, allografts have been shown to function even when the Ab rebound in the recipients. We have developed an in vitro model using human aortic endothelial cells (EC) and elucidated the ability of W6/32 HLA class I monoclonal Ab to provide signals following binding to MHC class I molecules. Using this model, we show that ECs undergo caspase 3-dependent cell death by apoptosis upon exposure to saturating concentrations of W6/32 and complement. In contrast, exposure of ECs to sub-saturating concentrations of W6/32 conferred resistance towards Ab/complement-mediated lysis that has been termed accommodation. Accommodated ECs exhibited a significant increase in the expression of anti-apoptotic genes Bcl-xL, Bcl-2 and Heme Oxygenase-1 and the induction of Phosphatidylinositol 3 kinase (PI3K) and cyclic adenosine monophosphate (cAMP) dependent protein kinase A activities that facilitate the phosphorylation of Bad at positions Ser(136) and Ser(112). In conclusion, exposure of sub-saturating concentrations of HLA class I Ab results in the induction of signals downstream that confers resistance to endothelial cells against Ab-complement mediated cell death. Together, the observations made in this study will provide the basis for delineating the molecular mechanisms involved in mediating accommodation and developing strategies to induce accommodation in grafts prior to transplantation in highly sensitized patients.

ABO Blood-Group System↗

PubMed2005

Novel in vivo murine model to study islet potency: engraftment and function.

Standard islet potency testing uses transplantation of islets under the kidney capsule in diabetic severe combined immunodeficient (d-SCID) mice. Even though it is possible to achieve normoglycemia in the majority of recipients by this method, the surgical procedure, by itself, is technically difficult and associated with an appreciable mortality of animals. In addition, the spatially limited renal subcapsular site restricts the mass of islet tissue that can be transplanted. Matrigel basement membrane matrix (MATRIGEL), extracted from a mouse sarcoma, is rich in angiogenic growth factors and has been shown to support the growth of mammalian cells using murine models. In this report we demonstrate that subcutaneous islet transplantation with MATRIGEL can effectively achieve normoglycemia and that this is a simple and reproducible model for in vivo islet potency testing in d-SCID mice that overcomes many drawbacks of the conventional method of kidney subcapsular islet transplantation.

Animals↗

PubMed2005

Prolonged limb allograft survival with CD 40 costimulation blockade, T-cell depletion, and megadose donor bone-marrow transfusion.

The purpose of this study was to determine the efficacy of a treatment regimen consisting of CD 40 costimulation blockade, T-cell depletion, and megadose donor bone marrow transfusion in the limb allograft model. C57Bl/6 mice underwent limb transplantation from Balb/c mice and received MR1 (anti-CD 40 ligand monoclonal antibody), and CD4(+) and CD8(+) T cell-depleting antibodies with and without 120 x 10(6) donor bone-marrow transfusion. Recipients treated only with antibodies showed rejection at 51.4+/-17 (mean+/-SEM) days, while those who also received donor bone marrow had allograft survival of 67+/-16.4 days, with a range up to 91 days. Treated specimens with rejection had less lymphocytic infiltration than untreated controls. Recipients of donor bone marrow also demonstrated early mixed chimerism, which disappeared after 1 month. While allograft survival was prolonged, tolerance was not achieved, and the mechanism of rejection was more consistent with a chronic process.

Animals↗

PubMed2005

Blood transfusions decrease the incidence of acute rejection in cardiac allograft recipients.

BACKGROUND: Cardiac transplant recipients frequently receive a large number of transfusions. The objective of this study was to determine whether there is an association between total number of blood transfusions and cardiac allograft rejection. METHODS: A retrospective analysis of all cardiac transplants between October 1, 1997, and December 31, 2001, was performed. Total number of transfusions, total number of rejection episodes Grade 3A or more, rejection-free survival, and overall survival were analyzed. Comparisons between patients bridged to transplantation with a Novacor left ventricular assist device (LVAD) and the primary transplant group were also made. RESULTS: Eighty-two patients were transplanted. Fifteen were bridged to transplantation, and 67 underwent primary heart transplantation. Age and sex were similar for the LVAD group and the primary transplant group (45 +/- 11 vs 47 +/- 15 years and 67% vs 58% male sex, respectively). Mean follow-up was 658 +/- 486 days for the LVAD group and 708 +/- 548 days for the primary transplant group. Transfusions received were 50 +/- 34 U of packed red blood cells for the LVAD group and 7 +/- 12 for the primary transplant group (p < 0.001). There were no differences in donor characteristics between the 2 groups. The incidence of acute rejection within 1 year was 27% for the LVAD group and 39% for the primary transplant group (p = .28). Freedom from rejection was 71% at 1 year in the LVAD group compared with 59% for the primary transplant group (p = 0.39). In all 82 patients, the total number of transfusions was inversely correlated with the development of acute rejection (p = 0.011). Survival was 80% and 62% for the LVAD group at 1 and 3 years after transplantation and 88% and 85%, respectively, for the primary transplant group (p = 0.045). CONCLUSIONS: The number of blood transfusions received by heart transplant recipients is inversely related with the number of acute rejection episodes.

Adult↗

PubMed2005

Tenascin-C, over expressed in lung cancer down regulates effector functions of tumor infiltrating lymphocytes.

PURPOSE: Extracellular matrix (ECM) proteins play a significant role in the survival and metastasis of cancer cells. Tenascin-C (TN-C) is an extracellular matrix protein and its large isoform has been implicated in tumor progression. Goal of this study was to analyze the expression of the small and large isoforms of TN-C in non-small cell lung cancer (NSCLC) and determine its functional significance. EXPERIMENTAL DESIGN: TN-C expression was studied in tumor and non-tumor tissue of patients with NSCLC at the mRNA and protein level. Immunomodulatory properties of the large isoform of TN-C were analyzed by determining its effect on lymphocyte proliferation and cytokine secretion by tumor-infiltrating lymphocytes (TIL). RESULTS: Quantitative real-time PCR analysis showed an eight-fold increase in the amount of large isoform in cancer cells compared to adjacent normal tissue. Expression at the protein level by Western blot analysis using a murine monoclonal anti-TN-C antibody detected increased expression of the large isoform in the tumor tissue that was correlated with the development of recurrent disease. A 18-fold increase in the expression of the large TN-C isoform was observed in patients with recurrent NSCLC compared to non-recurrent NSCLC. Large isoform of TN-C significantly inhibited anti-CD3 and mitogen-induced proliferation of human peripheral blood lymphocytes and interferon-gamma production by TIL isolated from the lung cancer specimens. CONCLUSIONS: Increased expression of TN-C observed at the site of tumor in NSCLC correlates with recurrence. TN-C inhibits TIL proliferation and cytokine thereby may promote tumor immune evasion and recurrence.

Blotting, Western↗

PubMed2005

A novel reduced-intensity stem cell transplant regimen for nonmalignant disorders.

Bone marrow transplantation (BMT) benefits nonmalignant diseases but is limited by regimen-related toxicity, graft-versus-host disease (GVHD), donor availability, and graft rejection (GR). To overcome some of these barriers, we developed a new conditioning strategy for these patients. In total, 16 patients received Campath-1H (33/48 mg; days -21 to -19), fludarabine (150 mg/m(2); days -8 to -4), melphalan (140/70 mg/m(2); day -3), and transplant using related/unrelated stem cells. GVHD prophylaxis included cyclosporine/methylprednisolone for cord cells. Other recipients also received methotrexate. Risk factors for GR included multiple transfusions (6), low stem cell numbers (1), and immunologic/metabolic disorders (3). Donor engraftment was present in 14/16 recipients. Neutrophils (ANC>0.5 x 10(9)/l) and platelets (>50 x 10(9)/l) engrafted at a median of 13 and 24 days. Two patients died of Pseudomonas sepsis prior to engraftment, one of CMV disease, and another of intracranial hemorrhage. With median follow-up of 281 days (78-907), 12/16 are stable/improved, or cured. Acute GVHD was absent (n=10) or mild and transient (grade1-2 skin) (n=4). There was no chronic GVHD. Toxicities were predominantly early infections within 100 days, and correlated with lymphopenia (CD4+ T and B cells). Stable engraftment and low incidence of significant GVHD, irrespective of age or stem cell source, make this reduced-intensity regimen attractive for nonmalignant disorders.

Adolescent↗

PubMed2005

TH1/TH2 cytokine profile of the immune response in limb component transplantation.

BACKGROUND: The purpose of this study was to define the cytokine secretion pattern during limb allograft rejection and to determine its correlation to differential tissue antigenicity of limb allograft components. METHODS: Twenty-five C57Bl/6 mice (H-2Kb) were randomized to six groups. The experimental groups were recipients of vascularized Balb/c mice (H-2Kd) allografts consisting of skin, muscle, whole limb, or limb with the skin removed or nonvascularized nerve allografts. The unmodified rejection response was studied by histology, flow cytometry, and ELISPOT assay to quantify IFN-gamma (Th1) and IL-4 (Th2) production. RESULTS: The greatest Th1 response was seen in the recipients of allografts composed of skin (973.3 +/- 93 spots/million spleen cells; mean +/- SEM), followed by whole limb (961.3 +/- 86/million), nerve (613.3 +/- 245/million), limb with skin removed (483 +/- 246/million), and then muscle (460 +/- 234/million). Recipients of skin, whole limb, and nerve allografts had the highest IFN-gamma:IL-4 ratios, or greatest Th1 deviation, of 3.1 +/- 0.4, 3.0 +/- 0.2, and 2.9 +/- 0.6, respectively. These were significantly greater than those that received muscle (0.9 +/- 0.3) and limb allografts with skin removed (1.0 +/- 0.4) (p < 0.05). CONCLUSIONS: The skin component produced the greatest Th1 activation of the immune response and appears to be a critical component of the overall antigenicity of the whole limb allograft, as evidenced by the Th2 shift seen when the skin was removed. Muscle produced the least Th1 differentiation, with nerve being intermediate.

Animals↗

PubMed2005

Combined treatment with CD40 costimulation blockade, T-cell depletion, low-dose irradiation, and donor bone marrow transfusion in limb allograft survival.

To determine the efficacy of a regimen based on CD40 costimulation blockade and donor bone marrow in the limb allograft model, C57Bl/6 mice received limb allografts from Balb/c mice and either no treatment or a combination of MR1 (anti-CD40 ligand monoclonal antibody), CD4+ and CD8+ T-cell-depleting antibodies, low-dose irradiation, and bone marrow transfusion from Balb/c donors for 1 or 2 weeks. Recipients treated for 1 week showed rejection at 38.2 +/- 5.4 (mean +/- SEM) days, while those treated for 2 weeks had allograft survival of 56.5 +/- 9.9, with a range up to 91 days. Histology demonstrated rejection which was less cell-mediated and suggestive of transplant vasculopathy. Differential rejection of skin occurred first. Thus, a combined regimen based on CD40 costimulatory blockade and donor marrow significantly prolonged allograft survival. However, tolerance was not achieved, and histology suggests chronic rejection as a possible cause of allograft loss.

Animals↗

PubMed2005

Immune mechanisms in the pathogenesis of bronchiolitis obliterans syndrome after lung transplantation.

Lung transplantation is recognized as the only viable treatment option in a variety of end-stage pulmonary diseases. However, the long-term survival after lung transplantation is limited by the development of obliterative bronchiolitis, and its clinical correlate bronchiolitis obliterans syndrome (BOS), which is considered to represent chronic lung allograft rejection. Histopathologically, BOS is an inflammatory process that leads to fibrous scarring of the terminal and respiratory bronchioles and subsequent total occlusion of the airways. The specific etiology and pathogenesis of BOS are not well understood. The current premise is that BOS represents a common lesion in which different inflammatory insults such as ischemia-reperfusion, rejection, and infection can lead to a similar histological and clinical outcome. However, the low incidence of BOS in non-transplanted individuals and the observation that early development of BOS is predicted by the frequency and severity of acute rejection episodes indicate that alloimmune-dependent mechanisms play a crucial role in the pathogenesis of BOS. The evidence presented in this review indicates that BOS is the result of humoral and cellular immune responses developed against major histocompatibility complex molecules expressed by airway epithelial cells of the lung allograft. This process is aggravated by alloimmune-independent mechanisms such as ischemia-reperfusion and infection. Currently, treatment of BOS is frequently unsuccessful. Therefore, a better understanding of the immunopathogenesis of BOS is of paramount importance toward improving long-term patient and graft survival after lung transplantation.

Antibody Formation↗

PubMed2005

Inhibition of obliterative airway disease development in murine tracheal allografts by matrix metalloproteinase-9 deficiency.

This study was designed to define the roles of matrix metalloproteinase (MMP)-2 and MMP-9 in obliterative airway disease (OAD) in heterotopic murine tracheal allografts, considered a suitable animal model for chronic lung allograft rejection. BALB/c tracheal allografts were transplanted into MMP-2-deficient (-/-) and MMP-9-/- mice. Also, wild-type recipients were treated with doxycycline, a nonspecific MMP inhibitor. After 10, 20 and 30 days, allografts were analyzed for OAD development, intragraft levels of MMP-2 and MMP-9 and the frequency and cytokine/chemokine production profile of alloreactive T cells. Allografts transplanted into wild-type mice developed OAD lesions within 30 days. These allografts revealed significant upregulation of both MMP-2 and MMP-9. Allografts transplanted into MMP-9-/- and doxycycline-treated recipients did not develop OAD. In contrast, allografts transplanted into MMP-2-/- mice developed OAD lesions with normal kinetics. Interestingly, MMP-9-/- recipients showed an enhanced T cell alloreactivity associated with an abnormal profile of cytokine/chemokine production. The enhanced T cell alloreactivity in MMP-9-/- mice was mediated by enhanced dendritic cell stimulatory capacity as well as enhanced T cell responsive capacity. These results suggest that MMP-9 plays an important role in the pathogenesis of OAD and may represent a target for the therapeutic intervention of chronic lung allograft rejection.

Airway Obstruction↗

PubMed2005

Induction of obliterative airway disease by anti-HLA class I antibodies.

Anti-HLA class I Abs are associated with the development of bronchiolitis obliterans syndrome (BOS) after lung transplantation. BOS is characterized histologically by fibrosis and airway epithelial cell apoptosis. We have previously shown that anti-HLA class I Abs induce proliferation, growth factor production and apoptosis in airway epithelial cells in vitro. Thus, this study was designed to determine whether anti-HLA class I Abs alone could induce obliterative airway disease (OAD) in heterotopic murine tracheal allografts. Toward this, HLA-A*0201-transgenic tracheal allografts were transplanted into Rag1-deficient mice treated with the W6/32 anti-HLA class I mAb. Allografts were harvested at days +30, +45, +60 and +90. Allografts displayed epithelial metaplasia by day +45, epithelial destruction and mild cellular infiltration by day +60 and complete lumen obliteration and moderate cellular infiltration by day +90. Anti-HLA class I Abs induced the production of several growth factors and growth factor receptors and apoptosis of parenchymal cells in the allograft. In addition, anti-HLA class I Abs induced macrophages and granulocytes infiltration. The results from this study demonstrate that anti-HLA class I Abs play an important role in the pathogenesis of OAD by inducing growth factor production, apoptosis and chemotaxis of inflammatory cells.

Animals↗

PubMed2005

Molecular mechanisms of chronic rejection following transplantation.

Although significant advances have been made in the field of organ transplantation, chronic rejection remains a major limiting factor for prolonged graft survival. The long-term survival and function of transplanted lungs are limited by the development of bronchiolitis obliterans syndrome (BOS). The 10-yr lung graft survival rate is only 18.6%. Aside from results of several clinical studies that strongly support the concept that BOS results from alloimmune-mediated injury, little is known regarding specific immune effectors or target molecules involved in the pathogenesis of BOS. Studies from our laboratory have provided evidence for the seminal role of CD4+ T-cells in the pathogenesis of obliterative airway disease (OAD) seen in BOS. Prior to any clinically detectable lesions, there is indirect antigen presentation of mismatched major histocompatibility complex (MHC) class I antigen and production of antibodies to these MHC antigens. Both MHC and minor histocompatibility antigen disparities can result in the development of OAD in animal models and preliminary results strongly suggest that peptide vaccination strategies may prevent OAD following heterotopic tracheal transplants. Using a newly developed orthotopic tracheal transplant model, we have obtained evidence for an important and probably exclusive role for airway epithelial cell injury as a primary mechanism for the immunopathogenesis of the development of OAD.

Animals↗