Rejection Of Allogeneic Transplants Research Articles

Induced Regulatory T Cells as Immunotherapy in Allotransplantation and Autoimmunity: Challenges and Opportunities.

Regulatory T cells (Tregs) play a crucial role in the homeostasis of the immune response. Tregs are mainly generated in the thymus and are characterized by the expression of Foxp3, which is considered the Treg master transcription factor. In addition, Tregs can be induced from naïve CD4+ T cells to express Foxp3 under specific conditions both in vivo (pTregs) and in vitro (iTregs). Both subsets tTregs and pTregs are necessary for the establishment of immune tolerance to self and non-self antigens. Although it has been postulated that iTregs may be less stable compared to tTregs, mainly due to epigenetic differences, accumulating evidence in animal models shows that iTregs are stable in vivo and could be used for the treatment of inflammatory disorders including autoimmune diseases and allogeneic transplant rejection. In this review, we describe the biological characteristics of induced T regs, the key factors involved in iTreg transcriptional, metabolic and epigenetic regulation and discuss recent advances for de novo generation of stable Tregs and their use as immunotherapeutic tools in different experimental models. Moreover, we discuss the challenges and considerations for the application of iTregs in clinical trials and describe the new approaches proposed to achieve in vivo stability, including functional or metabolic reprogramming and epigenetic editing.

The role of efferocytosis and transplant rejection: Strategies in promoting transplantation tolerance using apoptotic cell therapy and/or synthetic particles.

Recently, efforts have been made to recognize the precise reason(s) for transplant failure and the process of rejection utilizing the molecular signature. Most transplant recipients do not appreciate the unknown length of survival of allogeneic grafts with the existing standard of care. Two noteworthy immunological pathways occur during allogeneic transplant rejection. A nonspecific innate immune response predominates in the early stages of the immune reaction, and allogeneic antigens initiate a donor-specific adaptive reaction. Though the adaptive response is the major cause of allograft rejection, earlier pro-inflammatory responses that are part of the innate immune response are also regarded as significant in graft loss. The onset of the innate and adaptive immune response causes chronic and acute transplant rejection. Currently employed immunosuppressive medications have shown little or no influence on chronic rejection and, as a result, on overall long-term transplant survival. Furthermore, long-term pharmaceutical immunosuppression is associated with side effects, toxicity, and an increased risk of developing diseases, both infectious and metabolic. As a result, there is a need for the development of innovative donor-specific immunosuppressive medications to regulate the allorecognition pathways that induce graft loss and to reduce the side effects of immunosuppression. Efferocytosis is an immunomodulatory mechanism with fast and efficient clearance of apoptotic cells (ACs). As such, AC therapy strategies have been suggested to limit transplant-related sequelae. Efferocytosis-based medicines/treatments can also decrease the use of immunosuppressive drugs and have no detrimental side effects. Thus, this review aims to investigate the impact of efferocytosis on transplant rejection/tolerance and identify approaches using AC clearance to increase transplant viability.

2-D-gal Targets Terminal Fucosylation to Inhibit T-cell Response in a Mouse Skin Transplant Model.

Organ allograft rejection is mainly driven by T-cell response. Studies have shown that fucosylation plays essential roles in the immune cell development and function. Terminal fucosylation inhibitor, 2-deoxy-D-galactose (2-D-gal), has been reported to suppress immunoresponse of macrophages, but its effects on T-cell-mediated immune response and transplant rejection have not been fully explored. The terminal fucosylation level in T cells was detected through ulex europaeus agglutinin-I staining. The consequences of 2-D-gal on murine T-cell proliferation, activation, cytokine secretion, and cell cycle were investigated in vitro. T-cell receptor signaling cascades were examined. Last, mouse skin transplant model was utilized to evaluate the regulatory effects of 2-D-gal on T-cell response in vivo. The expression of fucosyltransferase1 was upregulated in CD3/CD28-activated T cells along with an elevation of α(1,2)-fucosylation level as seen by ulex europaeus agglutinin-I staining. Furthermore, 2-D-gal suppressed T-cell activation and proliferation, decrease cytokines production, arrest cell cycle, and prevent the activation of T-cell receptor signaling cascades. In vivo experiments showed that 2-D-gal limited T-cell proliferation to prolong skin allograft in mice. This was accompanied by lower level of inflammatory cytokines, and were comparable to those treated with Cyclosporin A. Terminal fucosylation appears to play a role in T-cell activation and proliferation, and its inhibitor, 2-D-gal, can suppress T-cell activation and proliferation both in vitro and in vivo. In a therapeutic context, inhibiting terminal fucosylation may be a potential strategy to prevent allogeneic transplant rejection.

Infusion of Some but Not All Types of Human Perinatal Stromal Cells Prevent Organ Fibrosis in a Humanized Graft versus Host Disease Murine Model

Allogeneic transplant rejection represents a medical complication that leads to high morbidity and mortality rates. There are no treatments to effectively prevent fibrosis; however, there is great interest in evaluating the use of perinatal mesenchymal stromal cells (MSCs) and other MSCs to prevent fibrosis associated with chronic rejection. In this study, we isolated human perinatal stromal cells (PSCs) from amnion (AM-PSC), placental villi (PV-PSC), and umbilical cord (UC-PSC) tissues, demonstrating the phenotypic characteristics of MSCs as well as a >70% expression of the immunomodulatory markers CD273 and CD210. The administration of a single dose (250,000 cells) of each type of PSC in a humanized graft versus host disease (hGvHD) NSG® murine model delayed the progression of the disease as displayed by weight loss and GvHD scores ranging at various levels without affecting the hCD3+ population. However, only PV-PSCs demonstrated an increased survival rate of 50% at the end of the study. Furthermore, a histopathological evaluation showed that only PV-PSC cells could reduce human CD45+ cell infiltration and the fibrosis of the lungs and liver. These findings indicate that not all PSCs have similar therapeutic potential, and that PV-PSC as a cell therapeutic may have an advantage for targeting fibrosis related to allograft rejection.

Pathways of Antigen Recognition by T Cells in Allograft Rejection.

The adaptive immune response leading to the rejection of allogeneic transplants is initiated and orchestrated by recipient T cells recognizing donor antigens. T-cell allorecognition is mediated via 3 distinct mechanisms: the direct pathway in which T cells recognize allogeneic major histocompatibility complex (MHC) molecules on donor cells, the indirect pathway through which T cells interact with donor peptides bound with self-MHC molecules on recipient antigen-presenting cells, and the recently described semidirect pathway whereby T cells recognize donor MHC proteins on recipient antigen-presenting cells. In this article, we present a description of each of these allorecognition pathways and discuss their role in acute and chronic rejection of allogeneic transplants.

Late Allograft Rejection: A Case Report

Recognition of donor antigens by recipient T cells in secondary lymphoid organs initiates the adaptive inflammatory immune response leading to the rejection of allogeneic transplants. We present a unique case of a 38-year-old male with late allograft rejection due to immunosuppressive cytotoxic therapy. There is limited literature available as well as management. This case highlights the need for further investigative research of this entity and its pathogenesis.

Mechanistic contributions of Kupffer cells and liver sinusoidal endothelial cells in nanoparticle-induced antigen-specific immune tolerance

The intravenous delivery of disease-relevant antigens (Ag) by polymeric nanoparticles (NP-Ags) has demonstrated Ag-specific immune tolerance in autoimmune and allergic disorders as well as allogeneic transplant rejection. NP-Ags are observed to distribute to the spleen, which has an established role in the induction of immune tolerance. However, studies have shown that the spleen is dispensable for NP-Ag-induced tolerance, suggesting significant contributions from other immunological sites. Here, we investigated the tolerogenic contributions of Kupffer cells (KCs) and liver sinusoidal endothelial cells (LSECs) to NP-Ag-induced tolerance in a mouse model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE). Intravenously delivered Ag-conjugated poly(lactide-co-glycolide) NPs (PLG-Ag) distributed largely to the liver, where they associated with both KCs and LSECs. This distribution was accompanied by CD4 T cell accumulation, clonal deletion, and PD-L1 expression by KCs and LSECs. Ex vivo co-cultures of PLG-Ag-treated KCs or LSECs with Ag-specific CD4 T cells resulted in PGE2 and IL-10 or PGE2 secretion, respectively. KC depletion and adoptive transfer experiments demonstrated that KCs were sufficient, but not necessary, to mediate PLG-Ag-induced tolerance in EAE. The durability of PLG-Ag-induced tolerance in the absence of KCs may be attributed to the distribution of PLG-Ags to LSECs, which demonstrated similar levels of PD-L1, PGE2, and T cell stimulatory ability. Collectively, these studies provide mechanistic support for the role of liver KCs and LSECs in Ag-specific tolerance for a biomaterial platform that is currently being evaluated in clinical trials.

CD103 promotes the proinflammatory response of gastric resident CD4+ T cell in Helicobacter pylori- positive gastritis

Abstract As an integrin found on T cell residence, CD103 is associated with the CD8+ T cell response in allogeneic transplant rejection, autoimmune diseases and cancer, but its role in infection and inflammation remains unclear. In this study, biopsy specimens of the gastric mucosa were obtained from patients with H. pylori-positive gastritis. We found that CD103 was highly expressed in CD4+T cells of the gastric mucosa from patients with H. pylori-positive gastritis. Mucosal resident CD103+CD4+T cells exhibited an increase in the CD45RO+CCR7− effector memory phenotype and high expression of the chemokines CXCR3 and CCR9 compared with those in CD103−CD4+ T cells. An In vitro coculture study demonstrated that H. pylori-specific antigen CagA/ VacA-primed dendritic cells (DCs) induced proliferation as well as IFN-γ, TNF and IL-17 production by CD103+CD4+ T cells from patients with H. pylori-positive gastritis. Furthermore, blocking CD103 with a neutralizing antibody reduced proliferation and IFN-g, TNF and IL-17 production by CD103+CD4+ T cells cocultured with DCs. Moreover, immunoprecipitation revealed that CD103 interacted with TCR α/β and CD3ζ, and activating CD103 enhanced the phosphorylation of ZAP70 induced by the TCR signal. Finally, increased T-bet and Blimp1 levels were also observed in CD103+CD4+ T cells, while activating CD103 increased T-bet and Blimp1 expression in CD4+ T cells. Our results explored the function of CD103 in gastric T cells from patients with H. pylori-positive gastritis, which may provide a therapeutic target for the treatment of gastritis

Comparing the Effects of the mTOR Inhibitors Azithromycin and Rapamycin on In Vitro Expanded Regulatory T Cells

Adoptive transfer of autologous polyclonal regulatory T cells (Tregs) is a promising option for reducing graft rejection in allogeneic transplantation. To gain therapeutic levels of Tregs there is a need to expand obtained cells ex vivo, usually in the presence of the mTOR inhibitor Rapamycin due to its ability to suppress proliferation of non-Treg T cells, thus promoting a purer Treg yield. Azithromycin is a bacteriostatic macrolide with mTOR inhibitory activity that has been shown to exert immunomodulatory effects on several types of immune cells. In this study we investigated the effects of Azithromycin, compared with Rapamycin, on Treg phenotype, growth, and function when expanding bulk, naïve, and memory Tregs. Furthermore, the intracellular concentration of Rapamycin in CD4+ T cells as well as in the culture medium was measured for up to 48 h after supplemented. Treg phenotype was assessed by flow cytometry and Treg function was measured as inhibition of responder T-cell expansion in a suppression assay. The concentration of Rapamycin was quantified with liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). Azithromycin and Rapamycin both promoted a FoxP3-positive Treg phenotype in bulk Tregs, while Rapamycin also increased FoxP3 and FoxP3+Helios positivity in naïve and memory Tregs. Furthermore, Rapamycin inhibited the expansion of naïve Tregs, but also increased their suppressive effect. Rapamycin was quickly degraded in 37°C medium, yet was retained intracellularly. While both compounds may benefit expansion of FoxP3+ Tregs in vitro, further studies elucidating the effects of Azithromycin treatment on Tregs are needed to determine its potential use.

CCR4 expression on host T cells is a driver for alloreactive responses and lung rejection.

Despite current immunosuppressive strategies, long-term lung transplant outcomes remain poor due to rapid allogenic responses. Using a stringent mouse model of allo-airway transplantation, we identify the CCR4-ligand axis as a central node driving secondary lymphoid tissue homing and activation of the allogeneic T cells that prevent long-term allograft survival. CCR4 deficiency on transplant recipient T cells diminishes allograft injury and when combined with CTLA4-Ig leads to an unprecedented long-term lung allograft accommodation. Thus, we identify CCR4-ligand interactions as a central mechanism driving allogeneic transplant rejection and suggest it as a potential target to enhance long-term lung transplant survival.

Janus-Faced Myeloid-Derived Suppressor Cell Exosomes for the Good and the Bad in Cancer and Autoimmune Disease

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells originally described to hamper immune responses in chronic infections. Meanwhile, they are known to be a major obstacle in cancer immunotherapy. On the other hand, MDSC can interfere with allogeneic transplant rejection and may dampen autoreactive T cell activity. Whether MDSC-Exosomes (Exo) can cope with the dangerous and potentially therapeutic activities of MDSC is not yet fully explored. After introducing MDSC and Exo, it will be discussed, whether a blockade of MDSC-Exo could foster the efficacy of immunotherapy in cancer and mitigate tumor progression supporting activities of MDSC. It also will be outlined, whether application of native or tailored MDSC-Exo might prohibit autoimmune disease progression. These considerations are based on the steadily increasing knowledge on Exo composition, their capacity to distribute throughout the organism combined with selectivity of targeting, and the ease to tailor Exo and includes open questions that answers will facilitate optimizing protocols for a MDSC-Exo blockade in cancer as well as for strengthening their therapeutic efficacy in autoimmune disease.

B Cell Depletion Prevents the Development of Memory T Cell Direct Alloreactivity After Allotransplantation.

Memory T cells (TMEM) play a crucial role in the rejection of allogeneic transplants and represents a major barrier to tolerance of allografts. Some evidence has been provided showing that mice lacking B cells (uMT mice) fail to develop anamnestic T cell immunity after allotransplantation. In the present study, we investigated the effects of in vivo pre-transplant B cell depletion using an anti-CD20 mAb (18-B12) on the development of TMEM responses in OT1 and OT2 mice (anti-OVA TCR transgenic mice) transplanted with an OVA Tg (mAct-OVA) skin graft. B cell depletion had no effect on acute graft rejection and it did not alter the percentages of CD4+ and CD8+ (CD44+CD62L+/-) TMEMs present in the recipients' blood and secondary lymphoid organs after transplantation. However, B cell-depleted mice mounted much higher early effector alloresponses than untreated mice but failed to develop any long-term CD4+ and CD8+ memory T cell response (direct alloresponse measured at d40 post-transplantation). Therefore, anti-CD20-mediated B cell depletion prevents the development of memory T cell direct alloreactivity after allotransplantation.

Engineering an ectopic thymus in the lymph node to induce central tolerance and long-term allograft acceptance (TRAN3P.896)

Abstract Background: Allogeneic transplant rejection is one of the major problems plaguing the field of organ transplants. Our previous studies have established the lymph node as a functional site for thymus transplant. In this study, we hypothesized that conditioning transplant recipients with thymic cells immune-matched to the donor will induce long-term acceptance of a subsequent allograft. Methods: We transplanted Balb/c-GFP thymuses into the lymph nodes of FAH-/- mice on a 129sv background. After 6 weeks, the animals were challenged with donor-matched skin grafts or hepatocyte transfer and monitored for long-term allograft acceptance. We also assessed tolerance induction by performing mixed lymphocyte reaction assays (MLR), immunostaining of native and ectopic thymus, as well as thymic dendritic cell (tDC)-T cell co-cultures. Results: Mice receiving thymus transplants successfully accepted subsequent allografts long-term. MLR reactions demonstrated Balb/c-specific tolerance in these mice. We also observed migration of cells (mostly tDCs) from the ectopic to the native thymus. tDC-T cell co-cultures revealed that migrating DCs from the ectopic as well as native thymus were instrumental in generating the increased numbers of Tregs observed in recipient mice. Conclusion: We were able to achieve long-term allograft acceptance in mice receiving thymic transplants, which was possibly mediated by the increased Treg induction associated with cross-talk between the two thymuses.

Perforin: an important player in immune response.

Perforin is a glycoprotein responsible for pore formation in cell membranes of target cells. Perforin is able to polymerize and form a channel in target cell membrane. Many research groups focus on the role of perforin in various diseases, immune response to bacterial and viral infections, immune surveillance and immunopathology. In addition, perforin is involved in the pathogenesis of autoimmune diseases and allogeneic transplant rejection. Natural killer (NK) cells and CD8-positive T-cells are the main source of perforin. However, CD4-positive T-cells are also able to express a low amount of perforin, when classic cytotoxicity is ineffective or disturbed.Polymerized perforin molecules form channels enabling free, non-selective, passive transport of ions, water, small-molecule substances and enzymes. In consequence, the channels disrupt protective barrier of cell membrane and destroy integrity of the target cell. This review will focus on mechanisms of action and structure of perforin. Also, in this review we discuss the problem of abnormal perforin production in diseases such as: hemophagocytic lymphohistiocytosis (HLH), leukemias and lymphomas, infectious diseases and autoimmune diseases. Better understanding of the role of these molecules in health and disease will open a new field of research with possible therapeutic implications.

Silencing the expression of platelet endothelial cell adhesion molecule‐1 prevents allogeneic T‐cell cytotoxicity

After solid organ transplantation, the endothelium is the first allorecognition checkpoint of the recipient's immune system. A major player at this interface is the platelet endothelial cell adhesion molecule-1 (PECAM-1), which is an immunoglobulin-like glycoprotein, involved in white blood cell migration, cellular adhesion, and signal transduction. The potential of preventing allorecognition at this interface was explored by knocking down PECAM-1 expression using RNA interference. Lentiviral-based vectors encoding short-hairpin RNA sequences specific for PECAM-1 transcripts were used for the transduction of monocytic and endothelial cell lines. Expression of PECAM-1 decreased by up to 80% at mRNA and protein levels on monocytic and endothelial cell lines. Antigen-binding capacity assays likewise showed up to 80% reduction of PECAM-1 expression on cell surfaces. In allogeneic T-cell stimulation assays, T cells stimulated with PECAM-1-silenced monocytes had granzyme B mRNA levels up to 85% lower than those in T cells stimulated with monocytes expressing nonspecific shRNA. Also, T-cell cytotoxicity showed to decrease significantly against PECAM-1-silenced monocytes versus those nonsilenced for PECAM-1. Moreover, the former T cells did not secrete interferon-γ and exhibited reduced proliferation. These findings suggest that permanent silencing of PECAM-1 expression is feasible and contributes to efficiently inhibiting the cytotoxic T-cell response to allogeneic target cells. Thus, targeting both the immunologic synapse at the regulatory interface and the lymphocyte migration might provide a new strategy to overcome allogeneic transplant rejection.

Comparison of the efficacy of tacrolimus and cyclosporine A in a murine model of dinitrofluorobenzene-induced atopic dermatitis

Tacrolimus (FK506) and cyclosporine A (Cys A) are immunosuppressive drugs used in the treatment of inflammatory diseases and for preventing rejection of allogeneic transplants. Tacrolimus forms a complex with FK506 binding protein (FKBP), and Cys A forms a complex with cyclophilin. These tacrolimus–FKBP and Cys A–cyclophilin complexes interact with calcineurin (CaN), thereby suppressing activation of T cells. In contrast, steroidal anti-inflammatory drugs suppress the immune system mainly via inhibition of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and the activating protein-1 (AP-1) pathway. Previously, we reported that tacrolimus, but not dexamethasone, reduced scratching behavior in a murine model of atopic dermatitis. To elucidate the mechanism involved in the inhibition of scratching behavior, we used a mouse model of allergic dermatitis to compare the characteristics of tacrolimus and Cys A treatment. We found that Cys A suppressed scratching behavior induced by application of 2,4-dinitrofluorobenzene, as did tacrolimus. In addition, both drugs attenuated increases in vascular permeability and scratching behavior induced by passive cutaneous anaphylaxis. These results indicate that inhibition of the CaN pathway plays an important role in tacrolimus- and Cys A-induced inhibition of scratching behavior in mice. Furthermore, we observed that CaN inhibitors suppressed mast cell-dependent allergic reaction.

Drak2 is required for T cell mediated allogeneic transplant rejection (145.9)

Abstract Drak2 is a serine threonine kinase that has previously been shown to negatively regulate activation of T cells through the T cell receptor. Additionally, T cells lacking Drak2 are hypersensitive to low levels of stimulation, but are surprisingly resistant to autoimmunity in an EAE model. Since it has been hypothesized that Drak2 deficient T cells die after activation, we tested the ability of these T cells to respond to allogeneic stimulation, which would mimic transplantation from an allogeneic donor. Using in vitro mixed lymphocyte reactions, Drak2-/- CD8+ T cells responded less to allogeneic stimulation compared to wildtype T cells when analyzed by CFSE dilution. Additionally, allogeneic tumors were used to determine the role of Drak2 during an in vivo allogeneic transplant. Rag2-/- gamma C-/-mice adoptively transferred with purified Drak2-/- T cells were not able to clear allogeneic tumors contrary to wildtype T cell recipients. Additionally, transgenic Bcl-xL expression in Drak2-/- T cells rescued the alloresponse, illustrated by restored ability to clear allogeneic tumors. Next, we aim to determine if Drak2 blockade is sufficient to prevent rejection in a pancreatic islet transplant model.

Prolonged Cardiac Allograft Survival in Mouse Model After Complement Depletion with Yunnan Cobra Venom Factor

Background Activation of the complement system is the leading mechanism that causes antibody-mediated acute rejection and hyperacute rejection after xenotransplantation. The major cause of acute rejection in allogeneic transplantation is the T cell–mediated specific immune response. We studied the effects of complement on acute rejection after cardiac allotransplantation using complement depletion with cobra venom factor (CVF) in the mouse. Materials and Methods The Balb/c-C57 mouse model of heterotopic cardiac allograft was used. The mice were divided into 2 groups, a control group and a CVF-treated group. After intravenous injection of CVF, the experimental group was observed for allograft survival time. Twelve mice from the control and experimental groups were sacrificed on days 3, 5, and 7 after the operation. The pathologic grade of acute rejection, deposition of C3 in tissue, extent of infiltration by CD4+ and CD8+ T cells, and expression of MHC-II, B7-1, and B7-2 were compared between the 2 groups. Results In the CVF-treated group, mean (SD) survival of the cardiac allograft was 26.2 (1.7) days, and in the control group was 8.4 (0.4) days ( P < .01). Pathologic examination and immunohistochemistry demonstrated that the grade of acute rejection, deposition of C3 in tissue, extent of infiltration of CD4+ and CD8+ T cells, and expression of MHC-II, B7-1, and B7-2 were significantly decreased in the CVF-treated group. Conclusion Depletion of complement in the serum with CVF inhibits acute cardiac allograft rejection in the mouse.

Intact LFA-1 deactivation promotes T-cell activation and rejection of cardiac allograft

Leucocyte function-associated antigen-1 (LFA-1) is known to be involved in immune reactions leading to allograft rejection. The role of deactivating LFA-1 in this context has not been investigated yet, although it is accepted that regulating LFA-1 activity is essential for T-cell function. Expressing LFA-1 locked in an active state in mice (LFA-1(d/d)) allowed us to investigate the in vivo function of LFA-1 deactivation for allograft rejection in a model of heterotopic cardiac transplantation. We provide in vivo evidence that regulating LFA-1 activity from an active to an inactive state controls antigen-specific priming and proliferation of T cells in response to allogeneic stimuli. Consequently, defective LFA-1 deactivation significantly prolonged cardiac allograft survival. Furthermore, reduced numbers of alloantigen-specific T cells and non-allo-specific innate immune cells within allografts of LFA-1(d/d) recipients indicate that expression of active LFA-1 impairs inflammatory responses involving all major leucocyte subpopulations. Taken together, our in vivo data suggest that LFA-1 deactivation is important for the formation of inflammatory lesions and rejection of cardiac allografts. Thus, the dynamic regulation of LFA-1 activity, rather than the mere presence of LFA-1, appears to contribute to the control of immune reactions inducing allogeneic transplant rejection.

Dual effects of the alloresponse by Th1 and Th2 cells on acute and chronic rejection of allotransplants

The contribution of direct and indirect alloresponses by CD4(+) Th1 and Th2 cells in acute and chronic rejection of allogeneic transplants remains unclear. In the present study, we addressed this question using a transplant model in a single MHC class I-disparate donor-recipient mouse combination. BALB/c-dm2 (dm2) mutant mice do not express MHC class I L(d) molecules and reject acutely L(d+) skin grafts from BALB/c mice. In contrast, BALB/c hearts placed in dm2 mice are permanently accepted in the absence of chronic allograft vasculopathy. In this model, CD4(+) T cells are activated following recognition of a donor MHC class I determinant, L(d) 61-80, presented by MHC Class II A(d) molecules on donor and recipient APC. Pre-transplantation of recipients with L(d) 61-80 peptide emulsified in complete Freund's adjuvant induced a Th1 response, which accelerated the rejection of skin allografts, but it had no effect on cardiac transplants. In contrast, induction of a Th2 response to the same peptide abrogated the CD8(+) cytotoxic T cells response and markedly delayed the rejection of skin allografts while it induced de novo chronic rejection of heart transplants. This shows that Th2 cells activated via indirect allorecognition can exert dual effects on acute and chronic rejection of allogeneic transplants.