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• W1988049670 abstract "The inducible co-stimulatory molecule (ICOS) has been shown to play a critical role in T-cell activation and differentiation, and the regulation of alloimmune responses in vivo. Using an MHC class II mismatched model of CD4+ T-cell-mediated rejection, we found that treatment of mice with DST and ICOS-B7h blockade induced long-term skin allograft survival and donor-specific transplantation tolerance. ICOS blockade, either during antigen priming or during the effector phase, previously shown to alter the outcome of the immune response, had a similar effect on graft survival. DST and anti-B7h mAb reduced the frequency of IFN-γproducing allospecific cells but did not produce deviation to a TH2 phenotype. In an adoptive transfer model using ABM TCR transgenic mice directly reactive to I-Abm12, DST and anti-B7h mAb reduced the number of allospecific CD4+ T cells and increased CD4+ T-cell apoptosis. These data demonstrate that DST and anti-B7h mAb induces transplantation tolerance to MHC class II mismatched skin grafts by a reduction of the alloreactive clone size that is, at least in part, dependent on apoptosis of host alloantigen-specific CD4+ T cells. The inducible co-stimulatory molecule (ICOS) has been shown to play a critical role in T-cell activation and differentiation, and the regulation of alloimmune responses in vivo. Using an MHC class II mismatched model of CD4+ T-cell-mediated rejection, we found that treatment of mice with DST and ICOS-B7h blockade induced long-term skin allograft survival and donor-specific transplantation tolerance. ICOS blockade, either during antigen priming or during the effector phase, previously shown to alter the outcome of the immune response, had a similar effect on graft survival. DST and anti-B7h mAb reduced the frequency of IFN-γproducing allospecific cells but did not produce deviation to a TH2 phenotype. In an adoptive transfer model using ABM TCR transgenic mice directly reactive to I-Abm12, DST and anti-B7h mAb reduced the number of allospecific CD4+ T cells and increased CD4+ T-cell apoptosis. These data demonstrate that DST and anti-B7h mAb induces transplantation tolerance to MHC class II mismatched skin grafts by a reduction of the alloreactive clone size that is, at least in part, dependent on apoptosis of host alloantigen-specific CD4+ T cells. Optimal activation of antigen-specific T cells requires signals delivered through the TCR and additional co-stimulatory molecules such as CD28 and CD154 (1Sayegh MH Turka LA The role of T-cell costimulatory activation pathways in transplant rejection..N Engl J Med. 1998; 338: 1813-1821Crossref PubMed Scopus (496) Google Scholar,2Rothstein DM Sayegh MH T-cell costimulatory pathways in allograft rejection and tolerance..Immunol Rev. 2003; 196: 85-108Crossref PubMed Scopus (199) Google Scholar). Engagement of CD28 on naïve T cells by B7-1 and B7-2 expressed on the surface of antigen-presenting cells (APCs) plays a critical role in initial T-cell priming, IL-2 production and cell cycle progression (3Jenkins MK Taylor PS Norton SD Urdahl KB CD28 delivers a costimulatory signal involved in antigen-specific IL-2 production by human T cells..J Immunol. 1991; 147: 2461-2466Crossref PubMed Google Scholar,4Harding FA McArthur JG Gross JA Raulet DH Allison JP CD28-mediated signalling co-stimulates murine T cells and prevents induction of anergy in T-cell clones..Nature. 1992; 356: 607-609Crossref PubMed Scopus (1500) Google Scholar). Like the CD28 pathway, ligation of APC-expressed CD40 by CD154 on activated T cells generates key signals for T-cell activation. However, although CD28-mediated co-stimulation appears to be required for primary T-cell activation, memory T-cell responses are CD28-independent (5Watts TH DeBenedette MA T cell co-stimulatory molecules other than CD28..Curr Opin Immunol. 1999; 11: 286-293Crossref PubMed Scopus (308) Google Scholar, 6London CA Lodge MP Abbas AK Functional responses and costimulator dependence of memory CD4+ T cells..J Immunol. 2000; 164: 265-272Crossref PubMed Scopus (267) Google Scholar, 7Coyle AJ Gutierrez-Ramos JC The expanding B7 superfamily: Increasing complexity in costimulatory signals regulating T cell function..Nat Immunol. 2001; 2: 203-209Crossref PubMed Scopus (367) Google Scholar), which indicates the presence of alternative co-stimulatory pathways. In addition, transplant rejection can proceed in the absence of CD28 co-stimulation (8Lin H Rathmell JC Gray GS Thompson CB Leiden JM Alegre ML Cytotoxic T lymphocyte antigen 4 (CTLA4) blockade accelerates the acute rejection of cardiac allografts in CD28-deficient mice: CTLA4 can function independently of CD28.J Exp Med. 1998; 188: 199-204Crossref PubMed Scopus (166) Google Scholar,9Yamada A Kishimoto K Dong VM et al.CD28-independent costimulation of T cells in alloimmune responses..J Immunol. 2001; 167: 140-146Crossref PubMed Scopus (107) Google Scholar). The inducible co-stimulatory molecule (ICOS), a member of the CD28 superfamily, is preferentially expressed on activated T cells (10Yoshinaga SK Whoriskey JS Khare SD et al.T-cell co-stimulation through B7RP-1 and ICOS..Nature. 1999; 402: 827-832Crossref PubMed Scopus (688) Google Scholar). ICOS binds to the ligand B7h, which is expressed on B cells and monocytes (10Yoshinaga SK Whoriskey JS Khare SD et al.T-cell co-stimulation through B7RP-1 and ICOS..Nature. 1999; 402: 827-832Crossref PubMed Scopus (688) Google Scholar). Studies using ICOS-/- mice (11Dong C Juedes AE Temann UA et al.ICOS co-stimulatory receptor is essential for T-cell activation and function..Nature. 2001; 409: 97-101Crossref PubMed Scopus (770) Google Scholar, 12McAdam AJ Greenwald RJ Levin MA et al.ICOS is critical for CD40-mediated antibody class switching..Nature. 2001; 409: 102-105Crossref PubMed Scopus (567) Google Scholar, 13Tafuri A Shahinian A Bladt F et al.ICOS is essential for effective T-helper-cell responses..Nature. 2001; 409: 105-109Crossref PubMed Scopus (596) Google Scholar) or ICOS blockade have shown that ICOS is necessary for the activation and function of effector T cells and plays a critical role in the differentiation of both TH1 (14Riley JL Blair PJ Musser JT et al.ICOS costimulation requires IL-2 and can be prevented by CTLA-4 engagement..J Immunol. 2001; 166: 4943-4948Crossref PubMed Scopus (108) Google Scholar, 15Sporici RA Beswick RL von Allmen C et al.ICOS ligand costimulation is required for T-cell encephalitogenicity..Clin Immunol. 2001; 100: 277-288Crossref PubMed Scopus (73) Google Scholar, 16Rottman JB Smith T Tonra JR et al.The costimulatory molecule ICOS plays an important role in the immunopathogenesis of EAE..Nat Immunol. 2001; 2: 605-611Crossref PubMed Scopus (246) Google Scholar, 17Guo J Stolina M Bready JV et al.Stimulatory effects of B7-related protein-1 on cellular and humoral immune responses in mice.J Immunol. 2001; 166: 5578-5584Crossref PubMed Scopus (42) Google Scholar) and TH2 (18Coyle AJ Lehar S Lloyd C et al.The CD28-related molecule ICOS is required for effective T cell-dependent immune responses.Immunity. 2000; 13: 95-105Abstract Full Text Full Text PDF PubMed Scopus (450) Google Scholar, 19McAdam AJ Chang TT Lumelsky AE et al.Mouse inducible costimulatory molecule (ICOS) expression is enhanced by CD28 costimulation and regulates differentiation of CD4+ T cells..J Immunol. 2000; 165: 5035-5040Crossref PubMed Scopus (375) Google Scholar, 20Tesciuba AG Subudhi S Rother RP et al.Inducible costimulator regulates Th2-mediated inflammation, but not Th2 differentiation,in a model of allergic airway disease..J Immunol. 2001; 167: 1996-2003Crossref PubMed Scopus (112) Google Scholar, 21Gonzalo JA Tian J Delaney T et al.ICOS is critical for T helper cell-mediated lung mucosal inflammatory responses..Nat Immunol. 2001; 2: 597-604Crossref PubMed Scopus (246) Google Scholar) cell types. Furthermore, Akbari et al. (22Akbari O Freeman GJ Meyer EH et al.Antigen-specific regulatory T cells develop via the ICOS-ICOS-ligand pathway and inhibit allergen-induced airway hyperreactivity..Nat Med. 2002; 8: 1024-1032Crossref PubMed Scopus (692) Google Scholar) have reported that ICOS ligation promotes IL-10-producing regulatory T cells that inhibit the function of antigen-specific T cells and attenuate the development of airway hyperreactivity. Previous work in transplantation models has shown that ICOS blockade prolonged cardiac allograft survival and suppressed intragraft T-cell activation and cytokine expression in a manner similar to that seen in ICOS-/- recipients (23Ozkaynak E Gao W Shemmeri N et al.Importance of ICOS-B7RP-1 costimulation in acute and chronic allograft rejection..Nat Immunol. 2001; 2: 591-596Crossref PubMed Scopus (287) Google Scholar).In addition, ICOS blockade has been shown to prolong allograft survival in a model of rat liver transplantation (24Guo L Li XK Funeshima N et al.Prolonged survival in rat liver transplantation with mouse monoclonal antibody against an inducible costimulator (ICOS)..Transplantation. 2002; 73: 1027-1032Crossref PubMed Scopus (49) Google Scholar) and facilitate long-term islet allograft survival when used in combination with other immunosuppressive drugs (25Nanji SA Hancock WW Anderson CC et al.Multiple combination therapies involving blockade of ICOS/B7RP-1 costimulation facilitate long-term islet allograft survival..Am J Transplant. 2004; 4: 526-536Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar).Recent data from our group (26Harada H Salama AD Sho M et al.The role of the ICOS-B7h T cell costimulatory pathway in transplantation immunity..J Clin Invest. 2003; 112: 234-243Crossref PubMed Scopus (125) Google Scholar) demonstrated that delayed blockade of ICOS-B7h during the effector phase of the alloimmune response was more effective in promoting long-term cardiac graft survival than early blockade during antigen priming. Furthermore, we have reported that early,but not delayed, ICOS-B7h blockade abrogated prolonged rat cardiac allograft survival induced by CTLA4Ig treatment, indicating the complex role and interactions of ICOS as a regulator of alloimmune responses in vivo (27Salama AD Yuan X Nayer A et al.Interaction between ICOSB7RP1 and B7-CD28 costimulatory pathways in alloimmune responses in vivo..Am J Transplant. 2003; 3: 390-395Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar). The capacity of co-stimulatory blockade to prevent acute allograft rejection and induce donor-specific transplantation tolerance is enhanced by administration of donor antigen in the form of donor-specific transfusion (DST) (28Lin H Bolling SF Linsley PS et al.Long-term acceptance of major histocompatibility complex mismatched cardiac allografts induced by CTLA4Ig plus donor-specific transfusion..J Exp Med. 1993; 178: 1801-1806Crossref PubMed Scopus (474) Google Scholar, 29Parker DC Greiner DL Phillips NE et al.Survival of mouse pancreatic islet allografts in recipients treated with allogeneic small lymphocytes and antibody to CD40 ligand..Proc Natl Acad Sci U S A. 1995; 92: 9560-9564Crossref PubMed Scopus (383) Google Scholar, 30Hancock WW Sayegh MH Zheng XG Peach R Linsley PS Turka LA Costimulatory function and expression of CD40 ligand, CD80, and CD86 in vascularized murine cardiac allograft rejection..Proc Natl Acad Sci U S A. 1996; 93: 13967-13972Crossref PubMed Scopus (374) Google Scholar, 31Sayegh MH Zheng XG Magee C Hancock WW Turka LA Donor antigen is necessary for the prevention of chronic rejection in CTLA4Ig-treated murine cardiac allograft recipients..Transplantation. 1997; 64: 1646-1650Crossref PubMed Scopus (101) Google Scholar, 32Markees TG Phillips NE Noelle RJ et al.Prolonged survival of mouse skin allografts in recipients treated with donor splenocytes and antibody to CD40 ligand..Transplantation. 1997; 64: 329-335Crossref PubMed Scopus (143) Google Scholar).The exact mechanism by which DST augments tolerance is uncertain, but provision of a strong TCR stimulus while blocking co-stimulatory signals may enhance development of anergy (33Quezada SA Fuller B Jarvinen LZ et al.Mechanisms of donorspecific transfusion tolerance: Preemptive induction of clonal Tcell exhaustion via indirect presentation..Blood. 2003; 102: 1920-1926Crossref PubMed Scopus (90) Google Scholar) or promote apoptosis (particularly of CD8+ T cells) (34Li Y Li XC Zheng XX Wells AD Turka LA Strom TB Blocking both signal 1 and signal 2 of T-cell activation prevents apoptosis of alloreactive T cells and induction of peripheral allograft tolerance..Nat Med. 1999; 5: 1298-1302Crossref PubMed Scopus (654) Google Scholar,35Iwakoshi NN Mordes JP Markees TG Phillips NE Rossini AA Greiner DL Treatment of allograft recipients with donor-specific transfusion and anti-CD154 antibody leads to deletion of alloreactive CD8+ T cells and prolonged graft survival in a CTLA4-dependent manner..J Immunol. 2000; 164: 512-521Crossref PubMed Scopus (192) Google Scholar).In addition, recent reports have suggested a role of regulatory T cells in peripheral tolerance achieved with DST and anti-CD154 mAb (36Iwakoshi NN Markees TG Turgeon N et al.Skin allograft maintenance in a new synchimeric model system of tolerance..J Immunol. 2001; 167: 6623-6630Crossref PubMed Scopus (60) Google Scholar, 37Sanchez-Fueyo A Weber M Domenig C Strom TB Zheng XX Tracking the immunoregulatory mechanisms active during allograft tolerance..J Immunol. 2002; 168: 2274-2281Crossref PubMed Scopus (155) Google Scholar, 38Sanchez-Fueyo A Tian J Picarella D et al.Tim-3 inhibits T helper type 1-mediated auto- and alloimmune responses and promotes immunological tolerance..Nat Immunol. 2003; 4: 1093-1101Crossref PubMed Scopus (578) Google Scholar). Here, we show that DST and anti-B7h mAb induces skin allograft tolerance in an MHC class II mismatched model of CD4+ T-cell-mediated rejection. We used a recently established adoptive transfer model system involving anti-BM12 (ABM) CD4+ TCR transgenic (tg) mice reactive to I-Abm12 (39Sayegh MH Wu Z Hancock WW et al.Allograft rejection in a new allospecific CD4+ TCR transgenic mouse..Am J Transplant. 2003; 3: 381-389Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar,40Sandner SE Salama AD Houser SL Palmer E Turka LA Sayegh MH New TCR transgenic model for tracking allospecific CD4 Tcell activation and tolerance in vivo..Am J Transplant. 2003; 3: 1242-1250Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar) to study the mechanisms underlying the induction of transplantation tolerance in this model. We demonstrate that treatment with DST and anti-B7h mAb reduces the alloreactive clone size and promotes apoptosis of host alloreactive T cells. C57BL/6 (B6)and B6.C-H2bm12/KhEg (bm12) mice were purchased from The Jackson Laboratory (Bar Harbor, ME). B6 nude mice were purchased from Taconic Farms (Germantown, NY). ABM TCR-tg mice have been described previously (41Backstrom BT Muller U Hausmann B Palmer E Positive selection through amotif in the alphabeta T cell receptor..Science. 1998; 281: 835-838Crossref PubMed Scopus (102) Google Scholar) and were maintained as a breeding colony in our animal facility. All mice were used at 6–12 weeks of age and were housed in accordance with institutionaland NationalInstitutes of Health guidelines. Full thickness trunk skin was collected from donor bm12 mice. A skin graft (1 x 1 cm in size) was grafted onto the dorsum of recipient mice, sutured with 6-0 prolene, and secured with Vaseline gauze and bandage for 7 days. In all adoptive transfer experiments using recipient B6 nude mice, two bm12 skin grafts were placed bilaterally onto the thoracic walls of recipients to allow for drainage into bilateral axillary and lateral axillary lymph nodes and thus recovery of sufficient numbers of alloantigen-specific T cells for flow cytometry experiments. Skin graft survival was monitored daily and rejection was defined as complete necrosis of the skin grafts. The anti-B7h hybridoma (HK5.3) was provided by Dr. H. Yagita (Juntendo University, Tokyo, Japan) and the mAb was manufactured by BioExpress Cell Culture Services (West Lebanon, NH). The mAb was given intra- peritoneally according to either of the following protocols: 0.5 mg mAb on the day of transplantation (day 0) 0.25 mg mAb on day 2, 4and 6 after transplantation (early treatment protocol); 0.5 mg mAb on day 4 and 0.25 mg mAb on day 6, 8 and 10 after transplantation (delayed treatment protocol). For preparation of DST, bm12 splenocytes were depleted of erythrocytes using ACKLysing buffer (BioWhittaker, Walkarsville, MD). On the day of transplantation, 5×106 RBC-free splenocytes from sex-matched bm12 donors were injected intravenously in a volume of 0.5 mL into wild type (wt) or nude B6 mice. In control experiments, bm12 splenocytes underwent irradiation (3000 rad) prior to DST. The technique for enzyme linked immunosorbent spot (ELISPOT) analysis has been described recently by our group and others (9Yamada A Kishimoto K Dong VM et al.CD28-independent costimulation of T cells in alloimmune responses..J Immunol. 2001; 167: 140-146Crossref PubMed Scopus (107) Google Scholar,42Matesic D Lehman PV Heeger PS High-resolution characterization of cytokine-producing alloreactivity in naive and allograftprimed mice..Transplantation. 1998; 65: 906-914Crossref PubMed Scopus (83) Google Scholar, 43Kishimoto K Dong VM Issazadeh S et al.The role of CD154-CD40 versus CD28-B7 costimulatory pathways in regulating allogeneic Th1 and Th2 responses in vivo..J Clin Invest. 2000; 106: 63-72Crossref PubMed Scopus (121) Google Scholar, 44Sho M Sandner SE Najafian N et al.New insights into the interactions between T-cell costimulatory blockade and conventional immunosuppressive drugs..Ann Surg. 2002; 236: 667-675Crossref PubMed Scopus (86) Google Scholar). Immunospot plates (Cellular Technology Ltd., Cleveland, OH) were coated with 4 µg/mL of anti-mouse IFN-γ (R4–6A2) capture mAbs in sterile PBS overnight. The plates were then blocked for 1.5 hours with sterile PBS containing 1 % BSA and washed with sterile PBS. RBC-depleted splenocytes (5 ×105 in 0.2 mL HL-1 medium [BioWhittaker] supplemented with 1% L-glutamine [BioWhittaker] and 10% FBS [Sigma], St. Louis, MO) were then placed in each well in the presence of 5 × 105 irradiated (3000 rad) allogeneic splenocytes (as APCs) and cultured for 24 hours at 37°C in 5% CO2. For detection of spots, 4 µg/mL of biotinylated anti-mouse IFN-γ (XMG1.2) mAb in PBS-Tween (0.05%)-BSA (1%) were used. Following 2h of incubation with streptavidin D horseradish peroxidase (DAKO, Carpin-teria, CA) diluted at 1:2000 in PBS–Tween–BSA. AllmAbs were purchased from BD Biosciences, (San Diego, CA). After washing, the plates were developed using 0.8 mL of 3-amino-9-ethylcarbazole (Sigma) mixed with 24 mL of 0.1-M sodium acetate containing 12 µL H2O2. The resulting spots were counted on a computer-assisted enzyme-linked immunospot image analyzer (T Spot Image Analyzer; Cellular Technology Ltd.). Adoptive transfer of ABM TCR-tg T cells was performed as previously described (40Sandner SE Salama AD Houser SL Palmer E Turka LA Sayegh MH New TCR transgenic model for tracking allospecific CD4 Tcell activation and tolerance in vivo..Am J Transplant. 2003; 3: 1242-1250Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). Briefly, spleens and lymph nodes were harvested from ABM TCR-tg mice and pooled single-cell leukocyte suspensions were prepared. CD4+ T cells were purified by negative selection using a magnetic cell separation system (Miltenyi Biotec, Auburn, CA). Typically, CD4+ T cells were isolated to >85% purity. An aliquot of cells was stained with anti-CD4, anti-TCR Vα2.1 and anti-TCR Vβ8.1, 8.2 and analyzed by flow cytometry to determine the percentage of TCR-tg CD4+ T cells. Typically, >90% of CD4+ T cells expressed the tg TCR. One day before skin transplantation, 2 × 106 TCR-tg T cells were injected intravenously into B6 nude mice. The draining bilateral axillary and lateral axillary lymph nodes were harvested 14 days after skin transplantation. Single-cell suspensions were prepared and cells were washed in PBS containing 2% FCS. Unlabeled anti-CD16/CD32 (anti-FcRγIII/anti-FcRβII) was used to block FcR binding. 1 × 106 cells were stained with PerCP-conjugated anti-CD4, FITC-conjugated anti-TCR Vα2.1 and biotinylated anti-TCR Vβ8.1, 8.2 followed by APC-conjugated streptavidin to identify the tg cells. All fluorochrome-labeled mAbs were purchased from BD Biosciences. Four-color flow cytometry was performed on a FACSCalibur (Becton Dickinson, San Jose, CA), and cells were analyzed using CellQuest acquisition software. A gate was set on live lymphocytes and between 1 × 105 and 5 × 105 events were collected. Leukocytes recovered from draining lymph nodes of adoptively transferred mice were stained for surface expression of Vα2.1 and Vβ8.1, resuspended in apoptosis buffer (BD Biosciences) according to manufacturer's instructions, and incubated with 7-AAD and PE-conjugated Annexin V (BD Biosciences) for 15 min at RT. A gate was set on Vα2+ Vβ8+ 7-AAD- lymphocytes and the percentage of Annexin V+ cells was determined by flow cytometry. Kaplan-Meier survival graphs were constructed and log-rank comparison of the groups was used to calculate p values. Student's t-test was used for comparisons of means. A p < 0.05 was considered statistically significant. We used a previously described blocking anti-B7h mAb (45Iwai H Kozono Y Hirose S Akiba H Yagita H Okumura K et al.Amelioration of collagen-induced arthritis by blockade of inducible costimulator-B7 homologous protein costimulation..J Immunol. 2002; 169: 4332-4339Crossref PubMed Scopus (135) Google Scholar) to study the role of ICOS-B7h blockade in MHC class II mismatched skin allograft rejection. The median survival time (MST) of bm12 (I-Abm12) skin allografts in untreated B6 (I-Ab) mice was 16 days (n = 9, Figure 1). Administration of anti-B7h mAb alone beginning treatment either on day 0 (early treatment; MST = 21 days, n = 6) or on day 4 (delayed treatment; MST = 24 days, n = 6) after skin transplantation did not prolong skin allograft survival in this model (Figure 1A). Treatment with 5 × 106 donor spleen cells plus control immunoglobulin (Ig) (MST = 15 days, n = 4) was similarly ineffective in prolonging skin graft survival (Figure 1B). In mice treated with 5 × 106 donor spleen cells on the day of transplantation and an early course of anti-B7h mAb, skin graft survival of >100 days was observed in 62.5% of recipients (n = 8; p < 0.0001 vs. untreated recipients, and p = 0.0003 vs. DST and control Ig-treated recipients). When mice were treated with 5 × 106 donor spleen cells on the day of transplantation and the course of anti-B7h mAb was delayed to day 4, long-term skin graft survival > 100 days was observed in 87.5% of recipients (n = 8; p < 0.0001 vs. untreated recipients, and p = 0.0003 vs. DST and control Ig-treated recipients).However, DST and delayed ICOS blockade did not significantly prolong skin graft survival compared with DST and early ICOS blockade. Mice that had accepted their primary bm12 skin grafts were tested for donor-specific transplantation tolerance. Such mice accepted a second donor-type bm12 skin graft indefinitely (MST > 100 days, n = 3 per group), but rejected third-party BALB/c skin grafts promptly (MST =12 days, n = 3 per group). Interestingly, and in keeping with previously published data (46Kast WM Van Twuyver E Mooijaart RJ et al.Mechanism of skin allograft enhancement across an H-2 class I mutant difference.Evidence for involvementof veto cells..Eur J Immunol. 1988; 18: 2105-2108Crossref PubMed Scopus (28) Google Scholar), the effect of DST was dependent on the presence of a radiosensitive cell population in that irradiation (3000 rad) of the adoptively transferred cells abrogated the effect of DST in combination with anti-B7h mAb. We first investigated the frequency of alloantigen-specific T cells responding to MHC class II mismatched alloantigen. Splenocytes were collected after 14 days from B6 recipients of bm12 skin grafts treated with early or delayed B7h blockade alone or in conjunction with DST, and an ELISPOT assay was performed to determine the frequency of TH1 (IFN-γ) and TH2 (IL-4) cytokine-producing allospecific cells. Interestingly, neither early nor delayed B7h blockade induced a significant change in the frequency of IFN-γ-producing alloreactive T cells compared with untreated recipients (Figure 2A). Similarly, the frequency of IFN-γ-producing cells in recipients receiving DST was comparable to untreated recipients. In contrast, DST in conjunction with either early or delayed B7h blockade reduced the frequency of IFN-γ-producing cells compared withuntreated recipients (p < 0.006). However, only DST and delayed anti-B7h mAb reduced the frequency of IFN-γ-producing cells compared with delayed anti-B7h mAb alone (p = 0.04) and DST alone (p = 0.04). No significant difference in the frequency of IL-4-producing cells was observed between the groups (Figure 2B). The isolated MHC class II mismatch present in the bm12 to B6 strain combination generates a rejection response that is primarily dependent on CD4+ T cells (39Sayegh MH Wu Z Hancock WW et al.Allograft rejection in a new allospecific CD4+ TCR transgenic mouse..Am J Transplant. 2003; 3: 381-389Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar,47Auchincloss Jr, H Mayer T Ghobrial R Winn HJ T-cell subsets,bm mutants, and the mechanisms of allogeneic skin graft rejection..Immunol Res. 1989; 8: 149-164Crossref PubMed Scopus (29) Google Scholar). We have recently established an adoptive transfer model system using ABM TCR-tg mice that allows us to track the behavior of alloantigen-specific CD4+ T cells during alloimmune responses in vivo (47Auchincloss Jr, H Mayer T Ghobrial R Winn HJ T-cell subsets,bm mutants, and the mechanisms of allogeneic skin graft rejection..Immunol Res. 1989; 8: 149-164Crossref PubMed Scopus (29) Google Scholar). The ABM TCR-tg system has been previously described (39Sayegh MH Wu Z Hancock WW et al.Allograft rejection in a new allospecific CD4+ TCR transgenic mouse..Am J Transplant. 2003; 3: 381-389Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar) and is a model of direct alloantigen presentation in which >90% of CD4+ T cells carry a tg TCR that directly recognizes the mutated MHC-II molecule I-Abm12. The specificity of TCR-tg T cells for bm12 alloantigen has been demonstrated both in vitro and in vivo (39Sayegh MH Wu Z Hancock WW et al.Allograft rejection in a new allospecific CD4+ TCR transgenic mouse..Am J Transplant. 2003; 3: 381-389Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar,40Sandner SE Salama AD Houser SL Palmer E Turka LA Sayegh MH New TCR transgenic model for tracking allospecific CD4 Tcell activation and tolerance in vivo..Am J Transplant. 2003; 3: 1242-1250Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar,48Rulifson IC Szot GL Palmer E Bluestone JA Inability to induce tolerance through direct antigen presentation..Am J Transplant. 2002; 2: 510-519Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar). The TCR-tg CD4+ T cells can be tracked with mAbs to TCR Vα2.1 and TCR Vγ8.1 by flow cytometry. We first used this adoptive transfer model system to determine the pattern of ICOS expression on alloantigen-specific CD4+ T cells in vivo. About 2 × 106 purified TCR-tg CD4+ T cells obtained from ABM TCR-tg mice were adoptively transferred into syngeneic nude B6 recipients. Adoptive transfer recipients were then transplanted with bm12 skin grafts. The draining lymph nodes were collected 3, 7,10 and 14 days following transplantation and TCR-tg CD4+ T cells were examined for ICOS expression (Figure 3). Before adoptive transfer, TCR-tg T cells did not express ICOS on the cell surface. TCR-tg CD4+ T cells demonstrated only minimal ICOS cell surface expression 3 days after transplantation. ICOS expression increased markedly on day 7, and remained up-regulated during skin graft rejection. We next used the ABM adoptive transfer model system to specifically investigate the mechanisms of tolerance induction with combined DST and anti-B7h mAb in this model. 2 × 106 purified TCR-tg CD4+ T cells obtained from ABM TCR-tg mice were adoptively transferred into nude B6 recipients. One group was not transplanted to control for homeostatic expansion of TCR-tg CD4+ T cells and received DST alone. The other three groups received bm12 skin grafts and either DST alone, DST and early anti-B7h mAb or DST and delayed anti-B7h mAb. Donor spleen cells were irradiated (3000 rad) before transfusion to avoid bm12 spleen cell homeostatic expansion or proliferation against TCR-tg CD4+ T cells. In control experiments, one group of adoptive transfer recipients was not transplanted; the other three groups received bm12 skin grafts and either no treatment, early anti-B7h mAb, or delayed anti-B7h mAb. The number of TCR-tg CD4+ T cells present in the draining lymph nodes in all groups was determined on day 14 after transplantation. Similar to our previous results using a blocking mAb to ICOS (26Harada H Salama AD Sho M et al.The role of the ICOS-B7h T cell costimulatory pathway in transplantation immunity..J Clin Invest. 2003; 112: 234-243Crossref PubMed Scopus (125) Google Scholar), both early and delayed ICOS blockade using anti-B7h mAb resulted in a significant reduction in expansion of alloantigen-specific CD4+ T cells (p < 0.05 vs. untreated recipients) (Figure 4A). The number of TCR-tg CD4+ T cells in the draining lymph nodes of skin graft recipients receiving DST was dramatically increased compared with ungrafted controls (p = 0.0004) (Figure 4B). Treatment with DST and early anti-B7h mAb (46.5 ± 23.7 × 104) or DST and delayed anti-B7h mAb (35.7 ± 15.4 × 104) reduced the number of TCR-tg CD4+ T cells in the draining lymph node" @default.
• W1988049670 created "2016-06-24" @default.
• W1988049670 creator A5005037626 @default.
• W1988049670 creator A5012124826 @default.
• W1988049670 creator A5028211848 @default.
• W1988049670 creator A5054858357 @default.
• W1988049670 creator A5060724793 @default.
• W1988049670 creator A5070494006 @default.
• W1988049670 creator A5076258810 @default.
• W1988049670 date "2005-01-01" @default.
• W1988049670 modified "2023-10-18" @default.
• W1988049670 title "Mechanisms of Tolerance Induced by Donor-Specific Transfusion and ICOS-B7h Blockade in a Model of CD4+ T-Cell-Mediated Allograft Rejection" @default.
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