Spontaneous Rejection Research Articles

Natural adjuvants: endogenous activators of dendritic cells.

Dendritic cells, the most potent antigen-presenting cells, need to be activated before they can function to initiate an immune response. We report here that, in the absence of any foreign substances, dendritic cells can be activated by endogenous signals received from cells that are stressed, virally infected or killed necrotically, but not by healthy cells or those dying apoptotically. Injected in vivo with an antigen, the endogenous activating substances can function as natural adjuvants to stimulate a primary immune response, and they may represent the natural initiators of transplant rejection, spontaneous tumor rejection, and some forms of autoimmunity.

Tobacco health warnings and smoking‐related cognitions and behaviours

To explore whether the introduction onto cigarette packs of new larger, more prominent health warnings in black on white would lead to an increase in: noticing warnings, thoughts about the effects of smoking, and consequent behaviours of not smoking a planned cigarette and/or prematurely stubbing out one already lit. In addition evidence was sought linking these effect to smoking cessation. Two national cross-sectional surveys of broadly representative samples of smokers: one about 2 weeks before the mandated introduction date of the warnings, and a follow-up 6 months later, part-way through implementation. A longitudinal subsample of smokers from the initial baseline survey was resurveyed at follow-up. In Australia, new health warnings and strengthened contents labelling of cigarette packets were mandated for cigarettes manufactured from 1 January 1995. Broadly representative samples of Australian smokers: 510 at baseline, and 512 at follow-up. Two hundred and forty-three of the baseline sample were also resurveyed. Self-report on effects of warnings and smoking cessation activity. In the cross-sectional sample at follow-up, 66% of smokers reported at least sometimes noticing the health warnings when taking out a cigarette (compared with 37% at baseline), and 14% reported they had refrained from smoking on at least one occasion as a result (compared with 7% at baseline). Not smoking as a result of noticing the (old) warnings at baseline was predictive of quitting at follow-up. Frequency of stubbing out cigarettes before they were finished as a result of thinking about smoking-related harm was not affected by the new warnings, but was predictive of making quit attempts. The new health warnings were more potent at stimulating both thoughts about negative effects of smoking and the appropriate consequent action of not smoking the planned cigarette. This is important as spontaneous rejection of cigarettes predicted subsequent cessation.

Current Status of Kidney Graft in 6 Recipients after Pregnancy

To determine whether pregnancy has an adverse influence on survival or graft function, a retrospective study was conducted. A total of 321 renal transplant(rTx) patients were followed on a day hospital basis of Tor Vergata University of Rome between January 1981 and April 1996. Out of 90 female subjects, 74 of childbearing age (less than 45 years) underwent the study. Six women had 7 pregnancies which resulted in 5 live births and two first trimester abortions. In one case the pregnancy occurred at 4 months after rTx: spontaneous abortion and acute rejection with graft loss occurred, for the four successful pregnancies the preconception serum creatinine (sCr) was 1.34 mg/dl (range: 1.3–1.4) and remained stable at the end of follow-up. The woman with two successful pregnancies had a sCr increase after second pregnancy, but it has remained stable at 4 yrs after rTx. The pt receiving rTx at 1981 with successful pregnancy after two yrs, reached ESRD 7 yrs after delivery because chronic rejection. Our data are consistent with other studies demonstrating no contraindication to pregnancy in women with stable renal transplant and controlled blood pressure. However, careful interdisciplinary monitoring is needed to reduce maternal and fetal risks.

CD28 is not required for rejection of unmanipulated syngeneic and autologous tumors.

To gain a better understanding of the requirement of CD28 co-stimulation in different types of T cell-dependent tumor rejection responses, we performed a series of syngeneic and autologous tumor rejection experiments on CD28 knockout mice. In a preimmunization-challenge model, virally-induced ALC lymphoma and methylcholanthrene-induced MC57X fibrosarcoma transplants were rejected similarly by syngeneic CD28 knockout and immunocompetent controls. ALC-specific cytotoxic T lymphocytes (CTL) and MC57X-specific tumor necrosis factor (TNF) release were induced in CD28 knockouts, although at a reduced level in the latter case. Secondly, the spontaneous regression of Moloney murine sarcoma virus (MMSV)-induced primary tumors in the autologous hosts occurred equally in CD28 knockouts and in immunocompetent control mice. A comparable virus-specific CTL response was generated in both, as revealed in cytolytic assays against RBL-5 targets. Thirdly, the spontaneous rejection of the B7-transfected EL-4 lymphoma by immunocompetent hosts was abrogated in CD28 knockout mice, since more than 82% CD28 knockouts developed tumors after inoculation with B7-transfected EL-4 cells. Our results therefore show that CD28 co-stimulatory molecules are not required for the rejection of unmanipulated syngeneic tumors in hyperimmunized hosts and the regression of MMSV-induced sarcoma in autochthonous hosts.

Echinococcosis

Hydatids, the intermediate stages, or metacestodes, of the tapeworm genus, Echinococcus, present a major immunological problem; they survive, grow and metastasize in immunized hosts which are protected against reinfection and possess effector mechanisms capable of killing the parasite. Explanations for this state of concomitant immunity have been made from investigations of avoidance strategies, genetics and quantitative hydatid growth. The latter study suggests that the host-parasite relationship is sustained as a dynamic equilibrium between parasite growth and acquired immunity, the balance being subject to mutual regulation and including the possibility of spontaneous rejection of the parasite. Two immunoregulatory, or cytokine-like, factors have been detected in hydatids of Echinococcus spp. One appears to be a mediator of the previously reported mitogenic effects of hydatids. Recent evidence has linked these effects to generation of T-suppressor populations. The second factor interferes with the interaction of macrophages and T-cells, mimics the effect of metacestode infection in impairing the accessory action of macrophages in lymphoproliferative responses, and is suppressive for rosette-forming cell responses against third-party antigens. It is suggested that these factors form part of a primary homeostatic mechanism regulating hydatid growth and immunity.

Defective lymphokine production by most CD8+ and CD4+ tumor-specific T cell clones derived from human melanoma-infiltrating lymphocytes in response to autologous tumor cells in vitro.

Human melanomas are infiltrated by tumor-reactive T lymphocytes. However, the ability of these cells to elicit a specific anti-tumor response in vivo remains to be established. Because lymphokine production is critical for T cell functions, we have analyzed the capacity of melanoma-specific tumor-infiltrating lymphocyte (TIL) clones to produce major lymphokines: interleukin-2 (IL-2), interferon-gamma (IFN-gamma) and interleukin-4 (IL-4), as well as tumor necrosis factor (TNF), in response to direct antigen presentation by autologous and allogeneic tumor cells. We report here that, upon stimulation by autologous melanoma cells, all TIL clones secreted TNF but only a few of them produced significant amounts of IL-2, IL-4 or IFN-gamma. Nonetheless, all these clones consistently produced two or three of these last lymphokines upon stimulation with phorbol myristate acetate and calcium ionophore, as well as IL-2 upon CD3 stimulation, showing the existence of three lymphokine profiles among them: Th1, Th0 and a profile characterized by IL-2 and IL-4, but not IFN-gamma secretion. Stimulation of TIL clones by allogeneic melanoma lines sharing the appropriate HLA-peptide complexes revealed that defective IL-2 production seemed to be a constant feature for some clones, while it was, for other clones, dependent on the antigen-presenting tumor cells. For this last type of clone, we further showed that defective IL-2 induction resulted from an LFA-3 defect of some melanoma cells or from distinct yet undefined defects of other melanoma lines. Our data suggest that defective lymphokine secretion may be an essential component of the in vivo failure of melanoma-reactive TIL to control tumor development. Interestingly both CD4+ and CD8+ TIL clones from one patient were fully activated by the autologous melanoma cells in vitro, supporting a potential role of such TIL in spontaneous or induced tumor rejection.

Treatment of hamster heart to rat xenotransplantation

Hamster-to-rat cardiac transplantation is an intensively studied model of primarily vascularized organ xenotransplantation. Spontaneous graft rejection is rapid compared to allografts, and has a graft histology that is characterized by morphological features decisively different from those observed in acute allogeneic rejection. However, the type of rejection can not be classified as hyperacute, according to rejection tempo and different morphology. Cardiac graft rejection occurs within three to four days in untreated recipients, which makes the model very suitable for the study of different immunosuppressing and immunomodulating treatment strategies. Inbred donor and recipient animals are commercially available and the use of rodents offers many advantages from a practical point of view, while microsurgical techniques allow highly reproducible results to be achieved in terms of surgical success and minimal failure rates. However, the impact of surgical trauma on graft survival and the influence of altered cardiac haemodynamics due to heterotopic transplantation, with a functional elimination of the left ventricle and subsequent reduced coronary blood flow, are essentially unknown. Graft survival data must therefore be interpreted cautiously with respect to possible graft outcome in other species--species combinations with a heart graft in an orthotopic position. A few publications from the 1970s and 1980s demonstrated that rejection in this model probably cannot be controlled by conventional immunosuppression. 1-4 Some years later Knechtle et al.~-7 achieved impressive long-term graft survival by combining total lymphoid irradiation (TLI) and cyciosporin A (CsA), but these results proved to be difficult to reproduce by others. This challenge, together with a general increased interest in xenotransplantation, has resulted in several studies during the last three to four years which have focused on reproducible control of rejection by different

Survival, function, morphology and serological aspects of rat renal allografts. Effect of short-term treatment with cyclosporine A, anti-CD4 and anti-interleukin-2 receptor monoclonal antibodies.

The aim of this study was to investigate the effect of short-term treatment with cyclosporine A (CyA) combined with anti-CD4 (OX-38) and anti-interleukin-2 receptor (OX-39) monoclonal antibodies (MAbs) on graft survival, graft function, morphology, and anti-donor antibody levels in a BN-to-LEW rat kidney transplantation model. Spontaneous rejection occurred at 9.3 days (range 9-10 d). Administration of CyA (12.5 mg/kg/d) for 14 days prolonged graft survival to 33 days (range 23-40 d, P less than 0.02). Supplementing with OX-38 and OX-39 100 micrograms/kg/d, given i.p. from days 0 to 7, further prolonged graft survival to 70 days (range 38- greater than 100 d, P less than 0.02 vs controls and CyA group). One of seven recipients had good graft function for more than 100 days. A three-fold increase of the MAb dosage did not improve mean graft survival (53.5 d), but three of eight recipients had well functioning grafts for greater than 100 days. Kidney function was characterized by reduced creatinine clearance, also in the recipients with long-term graft survival, and a defect in concentrating urine creatinine with subsequent pronounced increase in urinary output. Graft histology showed a complex pattern of interstitial alterations including mononuclear cell infiltration, fibrosis, tubular atrophy and vascular damage with intimal/endothelial cell hyperplasia and perivascular inflammation. In nine of 10 MAb-treated recipients with graft survival greater than 60 days, granular deposits of immunoglobulins and C3 were found by immunofluorescence microscopy (IFM). The deposits were localized in the glomerular capillaries and mesangium. IFM in MAb-treated control animals could not demonstrate any deposits. Flow cytometric evaluation of posttransplant serum samples against donor target cells showed increasing amounts of anti-donor antibodies until the time of rejection, while recipients with long-term graft function had moderately positive cross-matches up to two months after transplantation. Hereafter antibody titres decreased and cross-matches at the time of sacrifice were again negative. The morphological findings and the flow cytometric cross-match results seem to indicate a postponed antibody-mediated type of rejection. The reason why some kidney recipients showed decreasing antibody titres and stable long-term graft function is unclear.

Long-term survival of mouse corpus callosum grafts in neonatal rat recipients, and the effect of host sensitization.

Previous studies have suggested that the incidence of spontaneous rejection among immunogenetically mismatched neural transplants in neonatal recipients varies significantly depending on the cellular composition of the graft material. For example, neuron-rich grafts of embryonic mouse retina generally survive for extended periods without showing signs of rejection after implantation into neonatal rats, whereas cortical xenografts, which contain abundant glial and endothelial cells as well as neurons, typically undergo rejection 4-6 weeks after implantation. To determine whether the presence of donor glia is responsible for this high incidence of spontaneous rejection, we examined the fate of a non-neuronal graft material composed predominantly of xenogeneic glial cells (post-natal day 3, PD3, CD-1 mouse corpus callosum) implanted into the mesencephalon of PD1 Sprague-Dawley rats. The distribution and survival of donor astrocytes were assessed using a monoclonal antibody specific for a mouse astrocyte surface antigen, M2. Thirteen of 16 animals sacrificed within 2 months of implantation had detectable transplants. In these animals, M2-positive cells frequently migrated well away from body of the graft, clustering in large numbers in several characteristic regions of the host brain. Unlike cortical grafts of similar age, the vast majority (93%) of callosal transplants showed no histological signs of rejection or major histocompatibility complex antigen expression in and around the transplant-derived cells. As previously noted in the neonatal retinal transplant paradigm, however, well-integrated 1-month-old corpus callosum grafts could be induced to reject by appropriate sensitization of the host immune system, implying that the host was not immunologically tolerant to the foreign neural graft. With longer survival times in unsensitized hosts, a progressively smaller percentage of animals had detectable donor astrocytes (5 of 10 animals at 3 months postimplantation and 4 of 16 animals at 4 months); in those 9 animals with surviving grafts, only small numbers of M2-positive cells were seen within the graft bed and surrounding host brain. However, only 2 of the 26 "long-term" animals showed evidence of graft rejection. These results indicate that mouse astrocytes show characteristic patterns of migration into the host brain when implanted into neonatal rats; however, these xenogeneic cells have a limited duration of survival. The infrequency with which even subtle signs of spontaneous rejection were detected in animals that had received corpus callosum xenografts suggests that an immune-mediated process is unlikely to be responsible for the time-dependent elimination of the donor astrocytes.(ABSTRACT TRUNCATED AT 400 WORDS)

Non-adaptive cellular immune responses as studied in euthymic and athymic nude rats

The athymic nude (rnu) rat lacks a functional thymus and normal alloreactive T cells. These animals, therefore, have been widely used as tools for studying thymus-independent immune responses. The absence of functional T cells would, to most investigators, indicate that these rats have a defective cellular immune defence. However, although rnu rats accept organ allografts infinitely, they are nevertheless capable of rejecting allografts consisting of lymphocytes or bone marrow cells with increased vigour, and this via antibody-independent mechanisms. These rejection phenomena have operationally been termed allogeneic lymphocyte cytotoxicity (ALC) and allogeneic bone marrow cell cytotoxicity (ABC). Unlike organ allograft immunity this kind of rejection requires no presensitization of the recipient and is surprisingly rapid: it commences within a few hours of i.v. injection of the allogeneic cells and is usually complete by 24 h. Moreover, products coded for by genes within, or closely linked to the major histocompatibility complex (MHC), are clearly involved in the interaction between effector and target cells, as grafted cells from MHC-congenic rat strains are vigorously rejected. In contrast to the defective T cell immune responses in athymic nude rats, the natural killer (NK) cell function is not impaired, and it has been suggested that the spontaneous rejection of MHC-incompatible lymphohematopoietic cells is in fact mediated by NK cells. If the MHC antigens themselves serve as targets in this kind of allorejection, this hypothesis is in apparent contrast with the prevailing view that recognition by NK cells is not guided by, or directed against, MHC-antigens on the target cell surface. Aging athymic nude mice and rats generate cells that rearrange and express T cell receptor (TCR) genes, and this has raised the possibility that T cells or T-like cells in athymic nude animals are responsible for ALC and ABC. This possibility urged the device of an in vitro test system for identification and further characterization of the effector cells in these rejection phenomena. Under appropriate conditions, cells from the rnu rat spleen or liver with natural killer function, i.e. the ability to lyse certain kinds of tumor cells in vitro, are also spontaneously cytotoxic for allogeneic small lymphocytes and bone marrow cells in vitro. Furthermore, these cells can be grown in vitro in the presence of interleukin 2 (IL-2) to generate populations of lymphokine-activated killer (LAK) cells, and these cells have the same spectrum of alloreactivity in ALC and ABC as the native NK cells.(ABSTRACT TRUNCATED AT 250 WORDS)

MHC antigen expression and cellular response in spontaneous and induced rejection of intracerebral neural xenografts in neonatal rats

Fetal mouse retinae transplanted to the mesencephalon of neonatal rats generally survive for prolonged periods of time without immune suppression suggesting that such grafts enjoy a degree of immunological privilege. A small, but consistent percentage of these transplants, however, ultimately undergo spontaneous rejection. In addition, rejection can be induced by (1) systemically sensitizing the host to the donor antigens by placing a mouse skin graft or (2) producing a local degenerative process adjacent to the graft by removing the host eye contralateral to the side of the retinal transplant. To elucidate the immunological events that underly spontaneous and induced rejection in this system, we examined the distribution of lymphocytes, astrocytes, microglia, and cells expressing major histocompatibility complex (MHC) antigens in unrejected grafts, in transplants showing spontaneous rejection, and in grafts undergoing induced rejection. In unrejected grafts, increased astrocytic and microglial staining was seen around the photoreceptor layer of the graft and at the graft-host interface, but no lymphocytes and only occasional cells expressing MHC antigens were detected. In contrast, spontaneously rejecting grafts showed widespread MHC, lymphocytic, astrocytic, and microglial immunoreactivity that extended well beyond the limits of the transplant into the surrounding host brain. Skin graft-induced rejection produced a temporally consistent, comparatively localized enhancement of astrocytic, microglial and MHC immunoreactivity and infiltration of lymphocytes. Four to five days after skin grafting, before neural graft rejection was detectable histologically, MHC immunoreactivity was demonstrated within the transplant coinciding with the presence of small numbers of lymphocytes and an increase in microglial staining. By 8 days, grafts had undergone profound necrosis. Intense astrocytosis, microglial staining, MHC immunoreactivity, and perivascular lymphocytic cuffing were present within the graft and at the graft-host interface. With longer survival times, several of these changes were also detected within the visual pathways, suggesting that the regions to which the graft projected were also involved, though in a delayed fashion. After eye removal, the temporal pattern of rejection was more protracted and considerably less uniform than that seen after skin grafting. At 7 days, prominent microglial, astrocytic, and MHC immunoreactivity was seen in the area of distribution of the host optic axons within the superior colliculus and to a lesser extent around the graft itself, however, no infiltration of lymphocytes was detected. With longer survival times, an increasing percentage of grafts showed signs of overt rejection with perivascular cuffing by lymphocytes; however, even at 21 days, a small number of grafts remained free of lymphocytic infiltration, despite the presence of intense MHC, astrocytic, and microglial staining. We conclude that the different rejection models studied may involve fundamentally different triggers of the host immune system, but that in each case MHC expression may be the precedent step to graft rejection.

INSTABILITY OF NEURAL XENOGRAFTS PLACED IN NEONATAL RAT BRAINS

Embryonic mouse retinae placed in neonatal rat brains differentiate normally, form appropriate connections with the host brain, and may survive for longer than 1 year. However, such grafts are susceptible to rejection, either spontaneously or after challenge. Advanced spontaneous rejection of the transplant was identified in about 10% of the animals. In addition, two circumstances have been defined in which mouse retinal grafts can be subsequently induced to undergo rejection. One is following placement of a mouse skin graft on the flank of a rat that has received a retinal transplant in the brain, and the other is following removal of a host eye. After each of these procedures, the neural grafts become infiltrated with lymphocytes and undergo degeneration. It is proposed that this system may provide a useful approach not only for studying the immunology and genetics of neural transplantation, but also for examining the circumstances that precipitate the degenerative events associated with certain autoimmune diseases of the central nervous system.

Immunological analysis of a destructive pattern of intraocular tumor resolution.

Spontaneous rejection of syngeneic intraocular P91 mastocytoma occurred by a T cell-dependent immune process that produced extensive, irreparable damage to normal ocular tissue indicative of a delayed-type hypersensitivity (DTH) lesion. We investigated the contribution of other effector modalities in this tumor resolution. Antibody was not responsible for either tumor rejection of phthisis of the tumor-containing eye since passively transferred hyperimmune serum failed to produce either tumor rejection or the characteristic ocular lesions. Moreover, the destructive pattern of tumor rejection occurred in splenectomized hosts which had depressed anti-P91 serum antibody and in a congenic strain (B10.D2oSn) lacking the C5 complement component. The likelihood that tumor necrosis factor (TNF) was involved in this pathogenesis was also ruled out by the observation that P91 tumor cells were not susceptible to lysis by recombinant TNF. A different pattern of tumor resolution was observed when the opposite eye was challenged with tumor. In this case, the tumor was rejected without damaging any major ocular structures. Histological analysis demonstrated a mononuclear cellular infiltrate which was identified by immunohistology to be Thy 1+, Lyt 2+. Thus, although both forms of cell-mediated immunity are available to the host, only one predominated in each eye. These results suggest that unique immunological control mechanisms influence the outcome of tumor resolution in the eye.

Spontaneous tumor rejection is not always due to a complete cellular rejection

In this paper we have studied whether there is a correlation between efficacy of hosts to reject tumor cells spontaneously and the induction of cytotoxic macrophages in these recipients due to injection (immunization) with tumor cells. Results show that there is no cause-effect relationship between macrophage cytotoxicity and tumor rejection in vivo. This lack of cause-effect relationship is greatly influenced by differences in immunogenicity between the various tumor cell lines as well as by the release of tumor-factors by some of these tumors.

Correlation of in Vivo and in Vitro Immune Reactions Against the Intradermally Developing P-815 Mastocytoma in the Syngeneic Mouse

Although the highly malignant P-815 mastocytoma is fatal to syngeneic hosts when as few aauthor00 cells are injected intraperitoneally, growth of this tumor can be inhibited or suppressed when such cells are injected intradermally. The optimum cell number for transient growth inhibition or spontaneous rejection was found to be 10 4-10 5 cells. The phase of regression was perceptible by days 10-12. During tumor growth concomitant immunity developed as demonstrated by the suppression of a second tumor cell injection. The peak of the concomitant immunity was found between days 10-12. Immunity was adoptively transferable with spleen-or better lymph node cells from tumor bearing animals on days 10-12. Tumor regression and the development of concomitant immunity were paralleled by the appearance of lymphoid cells which in vitro kill the tumor target cells. Interestingly, lymphocytes from the draining lymph node were found to have a ten times higher killing capacity than lymphocytes from the spleen, whereas cells from the non-draining lymph nodes were not cytotoxic. Abrogation of cytotoxicity after treatment of effector cells with anti Thy-1.2 antibody and complement demonstrated that cytotoxicity was due to T cells. The suppression of the regression phase in vivo by treatment of the animals with Cyclosporin A suggested that T cells were also effective in vivo. However, despite the pronounced immunity in some animals, no definite immune reaction, either in vivo or in vitro, was observed in others.

Immune reactions of the syngeneic host after the intradermal injection of tumor cells and microsomes.

The P-815 mastocytoma is a methylcholanthrene induced, extremely malignant tumor of the DBA/2 strain of mice, characterized by a high proliferation rate and a high metastasizing capacity. The usual methodsof tumorspecific immunization proved unsuccessful in this experimental system not only in our hands but in other laboratories as well. P-815 cells therefore were considered free of tumor-specific antigens. P-815 cells metastasize abundantly into different organs after intraperitoneal (ip.) inoculation; however, they are never found in the skin. Therefore immunization by intradermal (id.) inoculation of untreated tumor cells was tried. This mode of application led to tumor growth and spontaneous rejection within 3–4 weeks in 80–100% of the treated animals when 104cells per animal were injected, a cell number corresponding to 100 LD100 when given ip. An immunity resulted from this treatment which could be demonstrated by the rejection without visible growth of 105 cells given id. or by the rejection of 500 cells given ip. This later dose corresponds to 5 LD100 (M. Bertschmarm et al. 1972).

Studies on thymus function. 3. Duration of thymic function.

The immune functions of neonatally thymectomized C3Hf mice exposed only temporarily to thymus function show a progressive decay with time in the absence of the thymus. The immune responses studied at different ages in the range of 100-600 days were: first-set rejection of H-2-compatible and incompatible skin allografts, second-set rejection of skin allografts, capacity of spleen cells to produce graft-versus-host reactions in F(1) hybrids, resistance to infection with mouse hepatitis virus, and response of spleen cells to phytohemagglutinin in vitro. These long-term studies had the purpose of determining the duration of the restoration induced by thymus function when the mice were exposed only temporarily to it. Different models were used but the two basic ones were: (a) mice grafted intraperitoneally at 15 days of age with a syngeneic thymus that was removed surgically at 10, 20, or 30 days after grafting, and (b) mice grafted at 15 days of age with allogeneic strain A thymoma or C57BL thymus, these representing situations in which there is spontaneous rejection of the restoring graft. In all the experimental models used, the animals were restored when tested at 100 days of age, but progressively became immunologically incapacitated at 200-300 days of age. From the more controlled experiments in which the restoring thymus graft was removed surgically, the following conclusions can be drawn. (a) A short exposure to a thymus graft can produce restoration of immune functions in neonatally thymectomized mice, but this restoration is not self-sustaining in the absence of the thymus and declines progressively with age. The decline usually starts at 200-300 days of age. (b) This was especially clear in experiments in which the same animal was tested twice in its lifetime for capacity to produce graft-versus-host reactions; these animals were competent at 100 days and became incompetent at 400 days of age. (c) The shortest period of thymic exposure studied was 10 days; if vascularization of the graft is taken into account, 2-3 days of thymic function are sufficient to produce restoration. (d) The immune decay observed in the thymectomized animals exposed temporarily to thymus was more profound than the physiological decay of immunity observed in control animals of similar age. (e) Of all the tests studied, the response of spleen cells to phytohemagglutinin was to be preserved the longest in animals exposed only temporarily to thymic function. The present results were interpreted in accordance with our previous findings indicating that a population of postthymic cells can be developed by temporary exposure of neonatally thymectomized animals to thymic function, but that this population is not self-sustaining in the absence of thymus and progressively decays by physiological attrition.

The role of immunity in the rejection of tumours induced by the MSV virus. The effect of antithymocyte serums

The rǒle of immunity in the rejection of tumours induced by the MSV virus. The effect of antithymocyte serumsRabbit anti mouse lymphoïd cell serum (ALS) facilitated the outgrowth of virus‐induced Rhabdomyosarcoma (MSV) in adult BALB/c and C57Bl/6 mice.Whereas all tumors induced in control mice completely regressed, most of the tumors induced in ALS inoculated mice grew progressively and killed the host. Frequency of positive mice was also greatly increased. Lymphocytes of mice immunized against MSV were able to inhibit the outgrowth of transplanted Moloney lymphoma cells. These experiments showed that spontaneous rejection of MSV induced tumors in adult mice is an immunological phenomenon mediated by immune lymphoïd cells.The rǒle of cellular immunity and antibody in tumor rejection are briefly discussed.

The literate revolution in Polynesia

essentially static. Closer study reveals rather its inherent mutability, exempli fied in such matters as the radical modification of weapons and military tactics,1 the invention of new vocabularies on the accession of a paramount chief,2 the introduction of the cult of Oro from Raiatea into Tahiti, or the quite spontaneous rejection of the past displayed in the overthrow of the great statues at Easter Island. More significant in the present context is the evidence, in the years immediately preceding the arrival of the English, of a mood of dissatisfaction and a general presentiment of revolution. Thus at Tahiti, for example, a seer, drawing no doubt on widespread traditions of the Spanish visitation in the Marquesas and the Tuamotu many years before, declared that foreigners would soon possess the land and that there would be an end of existing customs.8 And at Hawaii a contemporary prophet affirmed that a revelation would soon be made from heaven and the tabus of the country would be subverted.4 The Polynesians had at length explored and exhausted all the avenues open to a non-literate society and now sought an ampler world. In the event it was the European explorers of the 18th century who pointed the way. And it led to a material paradise which the peoples of Oceania made haste to enter. In 1767 the prime want at Tahiti was nails,5 no doubt since these were already familiar.6 By 1769 there was a brisk market in hatchets.7 And by 1791 the major demand was for axes, at a standard price,