Pre- and posttransplantation allosensitization in heart allograft recipients: major impact of de novo alloantibody production on allograft survival

The involvement of humoral response in allograft rejection has been suggested by both immunologic and histochemistry studies. In the present study, we explored the role of alloantibodies in a large cohort of heart allograft recipients followed for 15 years. Sequential samples of sera were obtained from 950 recipients of heart allografts before and after transplantation at the time when protocol endomyocardial biopsies were performed. The presence of anti-human leukocyte antigen (HLA) antibodies was investigated using complement mediated cytotoxicity and solid phase assay (SPA). Our data reveal an inverse correlation between the development of alloantibodies after transplantation and heart allograft survival. The 15-year graft survival was highest in patients who never developed alloantibodies (70%) or who displayed them only before transplantation (71%); graft survival in recipients who showed antibodies both before and after transplantation (56%), or only after transplantation (47%), was lower. The deleterious effect of antibodies on graft survival started 8 years after transplantation, suggesting that the production of de novo antibodies may have been triggered by some later event. We found that patients with de novo antibodies appearing more than 1 year after transplantation had the poorest survival. Furthermore, the development of de novo antibodies was preceded in 76% of these patients by cellular rejection grade 3 or higher, according to the International Society for Heart Transplantation (ISHT) grading criteria. Development of antibody-mediated rejection (AMR) had a significant negative impact on graft survival (16% in AMR(+) vs 63% in AMR(-) patients, p = 0.0008). Of the 23 patients with AMR, 21 displayed cytotoxic donor-specific antibodies (DSA) at the time of diagnosis, and in 18 of these cases SPA showed that they were directed against the donors' HLA. The data demonstrate that the detection of alloantibodies permits a better definition of AMR in heart allograft recipients. Identification of patients at risk for developing AMR is of great importance for early treatment of rejection episodes.     

A novel ELISA-based crossmatch procedure to detect donor-specific anti-HLA antibodies responsible for corneal allograft rejections

Previous studies had shown that donor-specific anti-HLA antibodies may highly influence the survival rate of corneal allografts, although the anterior chamber generally represents an immune-privileged compartment of the eye. We postulated that the introduction of a novel crossmatch procedure for the detection of donor-specific anti-HLA antibodies in recipients awaiting a corneal graft would be adequate to investigate their influence on the outcome of the graft survival. The Antibody Monitoring System (AMS) HLA class I & II crossmatch ELISA was adapted for the use of material from the outer scleral rim instead of blood lymphocytes to isolate the donors' HLA molecules. In case of detectable donor-specific anti-HLA class I and/or class II antibodies (DSA) this result was confirmed using an identification ELISA to specify the detectable recipient's anti-HLA antibodies. PCR-based genetic tissue typing of the donors was performed also using their outer scleral rims. 45 recipients of corneal grafts were analyzed for DSA prior to or after grafting, respectively. 75% of the recipients with preformed DSA exhibited immunological complications up to the complete graft loss in four cases during the first two months. In contrast 77% of the recipients without DSA did not show any complications during the follow up period of averagely 18months. Only two cases of graft loss were observed in this group after 17 and 23months, respectively. The results demonstrate the impact of preventing donor-specific anti-HLA antibodies which are for the first time reliably detectable in any laboratory's daily work using the adapted AMS-ELISA.     

The impact of pretransplant donor-specific antibodies on graft outcome in renal transplantation: a six-year follow-up study

OBJECTIVE:

The significance of pretransplant, donor-specific antibodies on long-term patient outcomes is a subject of debate. This study evaluated the impact and the presence or absence of donor-specific antibodies after kidney transplantation on short- and long-term graft outcomes.

METHODS:

We analyzed the frequency and dynamics of pretransplant donor-specific antibodies following renal transplantation from a randomized trial that was conducted from 2002 to 2004 and correlated these findings with patient outcomes through 2009. Transplants were performed against a complement-dependent T- and B-negative crossmatch. Pre- and posttransplant sera were available from 94 of the 118 patients (80%). Antibodies were detected using a solid-phase (Luminex®), single-bead assay, and all tests were performed simultaneously.

RESULTS:

Sixteen patients exhibited pretransplant donor-specific antibodies, but only 3 of these patients (19%) developed antibody-mediated rejection and 2 of them experienced early graft losses. Excluding these 2 losses, 6 of 14 patients exhibited donor-specific antibodies at the final follow-up exam, whereas 8 of these patients (57%) exhibited complete clearance of the donor-specific antibodies. Five other patients developed “de novo” posttransplant donor-specific antibodies. Death-censored graft survival was similar in patients with pretransplant donor-specific and non-donor-specific antibodies after a mean follow-up period of 70 months.

CONCLUSION:

Pretransplant donor-specific antibodies with a negative complement-dependent cytotoxicity crossmatch are associated with a risk for the development of antibody-mediated rejection, although survival rates are similar when patients transpose the first months after receiving the graft. Our data also suggest that early posttransplant donor-specific antibody monitoring should increase knowledge of antibody dynamics and their impact on long-term graft outcome.     

Effects of Monoclonal Anti-T Cell Antibodies on Rat Cardiac Allografts

Monoclonal antibodies reactive with different T lymphocyte antigens were administered to rats receiving heart allografts. Ox 19 antibodies (directed to the rat Ly 1 equivalent) and Ox 8 antibodies (directed to the rat CD8 equivalent) both prolonged graft survival, whereas W3/25 (anti-CD4), Ox 6 (anti-Ia), and W3/13 (anti-pan T) antibodies did not affect graft rejection. Immunohistological studies were carried out on spleen and graft specimens in order to analyse further the mechanisms behind the prolongation of graft survival. The observed almost complete absence of Ox 8-reactive cells in the spleen after treatment with Ox 8 antibodies corroborates earlier observations that injection of moderate amounts of Ox 8 antibodies leads to complete elimination of suppressor/cytotoxic T cells from peripheral lymphoid organs and blood. The present data on graft survival therefore both support the notion that suppressor/cytotoxic T cells are involved in graft rejection, and suggest that these cells are not the only ones involved. An unexpected and as yet unexplained finding was that Ox 8-reactive molecules were found in large numbers on various inflammatory cells as well as on certain myocytes in the grafted hearts that had experienced a prolonged graft survival due to treatment with Ox 8 or Ox 19 antibodies.     

Experimental corneal allograft rejection

The major findings regarding corneal allograft rejection in experimental animals are reviewed. The principal anatomic and biological feature of the cornea that dete rmines the immunologic privilege of this tissue is its avascularity. The surgical trauma of transplantation compromises the immunologic privilege, putting corneal allografts at risk for immune rejection. During the past 50 yr, rabbits, rats, and mice have been used extensively in the study of the process of immunologically mediated corneal allograft rejection. It is clear that the inflammation, and neovascularization of the graft that occurs following transplantation predisposes a corneal allograft to the classic cell-mediated immune rejection response. The antigenicity of cornea cells has been studied and has been found to be significantly lower compared to other cells and tissues. Rejection of acorneal allograft isacell-mediated processdirected against major histocompatibility, complex, antigens involving both CD4+T helper cells and CD8+ cytotoxic cells. The prevention of corneal allograft rejection depends on the development of topically applied compounds that can prevent inflammation and vascularization and inhibit the activation of T lymphocytes. Considerable progress has been made using immunomodulators, including blocking antibodies and soluble coreceptor blocking agents such as CTLA 4-Ig. Combinations of antiangiogenic, agents and immunomodul ators hold gre at promise for preventing corneal allograft rejection in patients.     

Selective immunosuppression with anti-interleukin 2 receptor-targeted therapy: helper and suppressor cell activity in rat recipients of cardiac allografts

(LEW X BN)F1 cardiac allografts are rejected within 8 days in unmodified LEW rats. ART18, a mouse anti-rat IgG1 monoclonal antibody which binds specifically in vitro to the interleukin 2 receptor (IL 2R) molecule expressed primarily on activated T cells, prolongs allograft survival in a dose-dependent fashion to ca. 3 weeks (p less than 0.001) after being administered for 10 days after transplantation. This effect was related to the specificity of the antibody for IL 2R, as therapy with ART62 (a monoclonal antibody recognizing MHC class I antigen but not binding the rat IL 2R) was ineffectual. Suppressor activity was detected in spleen cells of ART18-treated grafted hosts: in vivo, splenic T suppressor/cytotoxic fraction adoptively transferred into normal LEW improved donor-specific but not third-party test graft survival (17 days, vs. 8 days, respectively, p less than 0.001); in vitro, mixed lymphocyte reaction was profoundly but nonspecifically inhibited (less than 5% of test mixed lymphocyte reaction, p less than 0.001 as compared to acutely rejecting controls). In contrast, splenic T helper (Th) cells from ART18-treated hosts were functionally depressed, as noted by their passive transfer into immunologically anergic B recipients of cardiac allografts (rejection in ca. 40 days, vs. ca. 13 days after transfer of Th from specifically sensitized rats). ART18 treatment also resulted in diminished elaboration of IL 2 as compared to normal (p less than 0.005) or acutely rejecting hosts (p less than 0.001); however, a remarkable increase in the production of IL 3 occurred (p less than 0.001). These results demonstrate that IL 2R-targeted therapy of immunocompetent graft recipients produces a selective immune defect in which donor-specific T suppressor cells are spared, but Th cells attenuated or destroyed. Decreased elaboration of IL2 concomitantly augments the release of IL 3, a lymphokine which might play a role in suppressor effect in vivo. In addition, IL 2R-targeted therapy of the immunodeficient graft recipients abrogates the capacity of alloactivated T cells to re-establish acute immune responsiveness.     

Function of indoleamine 2,3-dioxygenase in corneal allograft rejection and prolongation of allograft survival by over-expression

Indoleamine 2,3-dioxygenase (IDO) suppresses T cell responses by its action in catabolising tryptophan. It is important in maintenance of immune privilege in the placenta. We investigated the activity of IDO in the cornea, following corneal transplantation and the effect of IDO over-expression in donor corneal endothelium on the survival of corneal allografts. IDO expression was analysed and functional activity was quantified in normal murine cornea and in corneas following transplantation as allografts. Low levels of IDO, at both mRNA and protein levels, was detected in the normal cornea, up-regulated by IFN-gamma and TNF. Expression of IDO in cornea was significantly increased following corneal transplantation. However, inhibition of IDO activity in vivo had no effect on graft survival. Following IDO cDNA transfer, murine corneal endothelial cells expressed functional IDO, which was effective at inhibiting allogeneic T cell proliferation. Over-expression of IDO in donor corneal allografts resulted in prolonged graft survival. While, on one hand, our data indicate that IDO may augment corneal immune privilege, up-regulated IDO activity following cytokine stimulation may serve to inhibit inflammatory cellular responses. While increasing IDO mRNA expression was found in allogeneic corneas at rejection, over-expression in donor cornea was found to significantly extend survival of allografts.     

Immunological aspects of cellular transplantology

The problem of surmounting the histocompatibility barrier and the mechanisms underlying the immune response to allo- and xenogeneic cells is discussed. Allogeneic grafts are recognized by T cells via direct and indirect pathways, while xenografts are recognized predominantly via the indirect pathway. Rejection of allografts is realized through recognition of foreign antigen by CD8 T cells, while xenografts are rejected after presentation of xenoantigens by host antigen-presenting cells to CD4 T cells. The differences in immune response to allo- and xenografts should be taken into consideration in the strategy of overcoming the histocompatibility barrier. The approaches to suppression of graft rejection are described in detail. Induction of antigen-specific tolerance proved to be the most optimal approach. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 125, No. 2, pp. 124–129, February, 1998     

Opposite effect of donor-specific immunization by blood or splenocytes on the survival of heart tissue transplants in strong versus weak histoincompatible combination in mice

Recipients of allogeneic heart tissue were pretreated intravenously with blood or injected intraperitoneally with spleen cells. In H-2 incompatible donor-recipient combination (BALB/c----CBA/H) donor-specific immunization, both with blood and spleen cells, resulted in acceleration of graft rejection. On the other hand, increase in graft survival was observed following donor-specific but not third-party blood pretreatment in mice compatible in H-2 complex but bearing different minor histoincompatible antigens (BALB/c----DBA/2).     

Unconventional lymphocytes involved in rejection of xenogeneic heart grafts

In this report, the efficacy of cyclosporine A and two monoclonal antibodies, anti-L3T4 and anti-Lyt-2.2, was assessed on first-set rejection of cardiac xenografts. Neither cyclosporine nor anti-Lyt-2.2 monoclonal antibody prolonged the survival of heart xenografts. Anti-L3T4 enhanced acceptance of rat hearts transplanted to C57BL/6 mice 5-fold relative to that observed in control recipients; it did not, however, prolong acceptance of hamster hearts transplanted to mice. Histologic analysis indicated that the cellular infiltrate within rejected hearts was composed of greater than 95% lymphocytes; of these, greater than 99% were Thy-1- and sIg-. These results suggest that rejection of xenogeneic hearts is mediated by unconventional lymphoid cells. This is discussed in the context of whether rejection of allografts and xenografts occur by similar or dissimilar mechanisms.     

免疫抑制剂用于角膜移植排斥反应的临床应用评价

背景：角膜移植免疫排斥反应是一个复杂的反应过程,一般包括宿主对异体组织抗原的致敏和宿主对异体组织抗原的反应两方面。角膜移植失败的主要原因是免疫排斥反应,有效地防治角膜移植术后免疫排斥反应的发生是眼科治疗中亟待解决的实际问题. 目的：文章就目前有关免疫抑制剂在角膜移植免疫排斥反应中的应用作一数据分析。 方法：通过计算机检索Scopus数据库中2002/2011有关免疫抑制剂在角膜移植免疫排斥反应中的应用的文献,检索词为“角膜移植(keratoplasty/corneal transplantation);免疫排斥反应(immunological rejection);免疫抑制剂(immunosuppressant);环孢素A(cyclosporine A,CsA);他克莫司(tacrolimus)或 FK506;雷帕霉素(rapamycin,RAPA)”,共检索文献192篇。 结果与结论：免疫排斥反应的发生是多因素参与的复杂过程,尤其高度血管化的角膜、感染性角膜溃疡、重复移植等高危角膜病变,术后出现排斥反应的概率明显增加,排斥反应发生的时间也相对较早,而且时间跨度较长。角膜移植排斥反应是一个复杂的过程,其预防及治疗已取得了多方面的进展,但排斥反应仍是角膜移植失败的首要原因,所以,专家们在不断尝试应用新的药物和治疗措施改善角膜移植的存活率,其最终目标是使受体在保持正常免疫应答能力的情况下,诱导产生/建立供体特异性免疫耐受。免疫抑制剂在角膜移植排斥反应中的应用不可或缺。     

Transplantation tolerance induced by antigen pretreatment and depleting anti-CD4 antibody depends on CD4+ T cell regulation during the induction phase of the response

Adult mice pretreated with donor-specific transfusion and depleting anti-CD4 antibody 28 days before transplant accept fully allogeneic heart grafts and become specifically tolerant without further treatment. The induction of tolerance in this model is not simply a function of CD4⁺ T cell ablation, but appears to depend on residual CD4⁺ T cells which escape depletion and engage donor alloantigen during a transient period of antibody blockade. To test the hypothesis that these CD4⁺ T cells might be responsible for regulating immune responses toward the graft, mice were reconstituted with naive recipient leukocytes at various times after pretreatment. Reconstitution either shortly after pretreatment or shortly after transplant had little effect on graft survival. However, when pretreated mice were given an additional dose of depleting anti-CD4 antibody at the time of transplant to target putative regulatory cells, naive leukocytes were able to cause acute graft rejection. These data suggest that in clinical transplantation specific T cell regulation might develop following pretreatment with antigen and non-depleting anti-CD4 antibodies. Such an approach could provide donor-specific unresponsiveness prior to transplant without the risks associated with sustained CD4⁺ T cell depletion.     

Gene therapy for the induction of chimerism and transplant tolerance

Technical advances in transplant surgery and the development of powerful and effective immunosuppressive drugs have contributed to the success of organ transplantation as a medical treatment for patients with end-stage diseases. Associated with this procedure, however, is a dependence on life-long immunosuppressive drugs, which are required to prevent graft rejection. These agents render the patient susceptible to infections, tumors and various side affects. The ability to achieve tolerance to organ grafts would free transplant patients from lifelong dependency on pharmacological agents with harmful side effects. Several laboratories have shown that tolerance can be achieved by the induction of mixed cell chimerism and/or by molecular chimerism achieved by gene transfer techniques prior to graft placement. Molecular chimerism, induced by transplantation of autologous bone marrow expressing either allo- or xenoantigens has the potential to induce tolerance without the development of graft vs. host disease. The application of gene transfer techniques to induce chimerism has been shown to reshape the immune repertoire by mechanisms that include clonal deletion, the induction of central tolerance or generation of regulatory T cells that would eliminate the need for immunosuppressive drugs. Optimization of this methodology for clinical use could therefore revolutionize the field of transplantation. This review summarizes the recent studies which have compared the efficacy of different vectors, conditioning regimens, and transduction conditions leading to new and improved techniques for the application of gene therapy to induce chimerism and transplant tolerance to both allografts and xenografts.     

Active Suppression of Host-Versus-Graft Reaction in Pregnant Mice. V. Kinetics,Specificity, and In Vivo Activity of Non-T Suppressor Cells Localized to the Genital Tract of Mice During First Pregnancy*

ABSTRACT: The fetus resulting from allogeneic mating in an outbred population such as man represents an antigenic graft against which the mother mounts an immune response. However, the type of immunity elicited by the “fetal allograft” does not appear to mediate graft rejection. This observation suggests that suppression of those types of immune responses that cause graft rejection may account for fetal survival. Allografts placed experimentally within the uterus appear to enjoy prolonged survival compared to grafts at other sites, and this latter finding suggests that localized suppression of graft rejection may exist within the uterus at the maternal-fetal interface. Previous studies have shown that suppressor cells which develop in the lymph nodes draining the uterus (DLN, paraaortic and renal lymph nodes draining the uterus) of allogeneically mated C3H and CBA strain mice are small lymphoid cells that sediment at 3 mm/h in unit gravity; arise early during first pregnancy, reaching maximum activity near the time of implantation (“grafting”); selectively inhibit the generation of cytotoxic T cells (cytotoxic T lymphocyte—CTL—or killer T cells) in vitro and in vivo; and are absent in the DLN of CBA mice which spontaneously resorb their litters. Furthermore, this suppressor cell population appears to be concentrated within the uterine decidua, and both DLN and decidual suppressor cells are under hormonal control. We now report that initial onset of suppression in decidua occurs more rapidly than in DLN after mating. The suppressor cell population in both DLN and decidua is resistant to destruction by anti-T serum plus complement and anti-Ly sera plus complement, and preliminary studies show that suppressor cell activity is associated with a population of granulated small lymphocytes. A soluble suppressor activity can be obtained from the decidual lymphoid population similar to that obtained in studies of the DLN suppressor cell. Small numbers of suppressor cells can prevent the infiltration of sponge matrix allografts by cytotoxic T cells in vivo. Thus, a non-T suppressor cell population may accumulate within the uterus and protect the fetal allograft from cell-mediated immune rejection.     

Blockade of the OX40 ligand prolongs corneal allograft survival

Although corneal transplantation is one of the most common tissue transplantations and is known to have a high graft acceptance rate, occasional corneal graft rejection remains a cause of blindness. OX40, a member of the TNF receptor superfamily, is expressed on activated T cells, and transmits a costimulatory signal by binding to OX40 ligand (OX40L) expressed on several cells with antigen-presenting functions. Using a blocking monoclonal antibody (mAb) against murine OX40L, we investigated the role of OX40 in a murine model of corneal transplantation. C3H/He mouse corneas were transplanted to BALB/c mice orthotopically. Administration of anti-OX40L mAb significantly reduced allograft rejection, and increased graft survival rate to 40% at 8 weeks after transplantation, while all corneas were rejected within 5 weeks in control IgG-treated mice. Similar reduced rejection was observed when wild-type donor corneas were transplanted to OX40L-deficient recipients. In vitro study revealed that the anti-OX40L mAb treatment reduced proliferative response and IFN-gamma production of draining lymph node cells in response to stimulation with donor alloantigen. These results demonstrate that OX40L blockade is effective for prolongation of corneal allograft survival by inhibiting recipient T cell activation.     

Immunopathology of liver transplantation

Liver transplantation has become an accepted therapeutic modality for many patients with end-stage liver diseases. Compared to other solid organ allografts, the immunopathological mechanisms involved in the original disease, rejection reactions, and potentially recurrent original diseases are seemingly more complex. The spontaneous acceptance of animal liver grafts without immunosuppression, the induction of donor-specific tolerance after liver grafting, its seeming resistance to hyperacute or primary humoral rejection, the dualistic effect of major histocompatibility matching on graft survival, functional and immunohistopathologic aspects of rejection reactions, infections, and the complexities involved in analysis for the potential of recurrent disease are discussed. Although many issues remain unresolved, liver transplantation offers a unique opportunity for studying the role of the immune system in both transplantation biology and primary liver disease.     

抗B7-1和抗CD40L单抗延长小鼠皮肤移植物存活实验研究

将C57BL/6小鼠腹部全层皮肤移植于BALB/c小鼠中段背部,实验分组(每组7只小鼠):1.B7-1功能性单抗(4E5)治疗组;2.抗CD40L单抗(4F1)治疗组;3.4E5+4F1治疗组,各单抗以20㎎/㎏的剂量注入腹腔内;4.空白对照组,只注射同等量的生理盐水。注射时间为移植后0﹑1﹑3﹑5d,观察移植皮肤排斥情况。于术后第6天分别杀死各组受体和供体鼠,取受体脾细胞与供体作混合淋巴细胞反应(MLR)。收集培养6d的初次反应细胞,检测再次MLR。结果发现,与对照组相比,各单抗治疗组皮肤移植物存活时间延长(P<0.05﹚;与各单独应用4F1和4E5相比,联合使用4F1和4E5产生一定的协同作用,但未能进一步延长移植物的寿命(P>0.05)。初次单向MLR:4F1﹑4E5和4F1+4E5治疗组受体T淋巴细胞在MLR中表现对供体淋巴细胞特异性低反应性,能有效抑制T细胞对同种异体抗原的初次应答。再次单向MLR:4F1﹑4E5﹑4F1+4E5对供体淋巴细胞在再次反应中仍保持着对同种抗原的反应性,与对照组无显著差异,未能诱导特异性免疫耐受。综上结果证实,anti-CDB7-1mAb(4E5)和anti-CD40LmAb(4F1)作为新型免疫抑制剂,在一定程度上抑制细胞免疫应答,干预排斥反应。     

Immunology of renal allograft rejection

Allograft rejection remains the critical problem of renal transplantation. The immunologic mechanisms that underlie renal allograft rejection are heterogeneous and involve the humoral and cellular limbs of the immune response. Antibody-mediated hyperacute rejection is now rare owing to improved prospective cross-matching. Chronic rejection, characterized by intrarenal arterial fibrosis, is still poorly understood. Knowledge of the afferent and efferent processes involved in rejection has led to effective therapeutic and experimental strategies that employ monoclonal antibodies and other pharmacologic agents to reverse, or prevent, acute allograft rejection. In addition, allospecific tolerance has been achieved experimentally and clinically in a variety of manners. Preliminary studies on the mechanism of allograft tolerance induced by donor-specific blood transfusions before transplantation suggest a role for an immunoregulatory cell population that specifically down regulates cytotoxic lymphocyte responses to donor antigens in some recipients. A role for noninherited maternal antigens and anti-idiotypic antibodies in down regulating immune responses to allografts have also been reported by several studies. An improved understanding of allograft rejection and tolerance may identify approaches to prolong allograft survival without the morbidity and mortality associated with present-day immunosuppression.     

Role of anti-vimentin antibodies in allograft rejection

Production of anti-vimentin antibodies (AVA) after solid organ transplantation are common. Although classically thought to be expressed mainly within the cytosol, recent evidence demonstrates that extracellular or cell surface expression of vimentin is not unusual. This review examines the evidence to assess whether AVA contribute to allograft pathology. Clinical studies suggest that AVA are associated with cardiac allograft vasculopathy in heart transplant recipients. Studies in non-human primates confirm that production of AVA after renal and heart transplantation are not inhibited by Cyclosporine. Experimental studies have demonstrated that mice pre-immunised with vimentin undergo accelerated acute rejection and vascular intimal occlusion of cardiac allografts. Adoptive transfer of hyperimmune sera containing AVA into B-cell-knock-out mice caused accelerated rejection of allografted hearts, this is clear evidence that antibodies to vimentin accelerate rejection. AVA act in concert with the alloimmune response and AVA do not damage syngeneic or native heart allografts. Confocal microscopy of allografted organs in vimentin immunised mice shows extensive expression of vimentin on endothelial cells, apoptotic leukocytes and platelet/leukocyte conjugates, co-localising with C4d. One explanation for the ability of AVA to accelerate rejection would be fixation of complement within the graft and subsequent pro-inflammatory effects; there may also be interactions with platelets within the vasculature.     

Temporal pattern of host responses against intrastriatal grafts of syngeneic,allogeneic or xenogeneic embryonic neuronal tissue in rats

The host response to immunologically incompatible intrastriatal neural grafts was studied using immunohistochemical techniques. Dissociated ventral mesencephalic tissue from embryonic donors of either syngeneic, allogeneic or xenogeneic (mouse) origin was stereotaxically implanted into adult rats. The brains were analysed 4 days, 2 weeks or 6 weeks after grafting with antibodies against the following antigenic structures: major histocompatibility complex (MHC) class I antigens; MHC class II antigens; complement receptor (CR) 3 (marker for microglia and macrophages); helper T-lymphocyte antigen-cluster of differentiation (CD) 4; cytotoxic T-lymphocyte antigen-CD8; tyrosine hydroxylase (TH) (marker for transplanted dopaminergic neurons). The number of surviving TH-positive cells was not different at the various time points in either the syngeneic or allogeneic groups, whereas the xenogeneic cells were all rejected by 6 weeks.The host reactions were similar in character in the syngeneic and allogeneic groups. At 4 days after implantation, there were increased levels of expression of MHC class I and II antigens. In and around the grafts, there were cellular infiltrates consisting of activated microglia, macrophages, CD4- and CD8-positive lymphocytes. At 6 weeks, MHC expression was reduced and the cellular infiltrates had subsided with only low numbers of activated microglia cells and CD8-positive lymphocytes remaining. In the xenogeneic group, at 4 days, some grafts contained cavities, possibly reflecting acute rejection. At later stages, the xenografts were heavily infiltrated by macrophages, activated microglial cells and T-lymphocytes, and at 6 weeks all the xenografts were rejected.Taken together, the results suggest that there is an inflammation caused by the implantation process which leads to an accumulation of host defence cells. This, in turn, leads to increased MHC expression in and around the grafts. In syngeneic grafts, these reactions are short lasting and weak; for allografts slightly more pronounced and longer lasting than syngeneic grafts, but not sufficient to cause rejection. For xenografts, the reactions are more intense and lead to transplant rejection. Thus, a strong sustained inflammatory response may be an important determinator for the failure of histoincompatible neural grafts. It can be speculated that a short-term anti-inflammatory treatment of graft recipients may be a sufficient immunosuppressive regimen to allow long-term graft survival.