Fototerapia, una alternativa para el manejo de la forma crónica de enfermedad del injerto contra huésped (EICH) / Phototherapy for the management of chronic graft-vs-host disease

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Differential sensitivity of T lymphocytes and hematopoietic precursor cells to photochemotherapy with 8-methoxypsoralen and ultraviolet A light.

The combination of 8-methoxypsoralen (8-MOP) and long wave ultraviolet radiation (UV-A) has immunomodulatory effects and might abolish both graft-vs-host and host-vs-graft reactions after allogeneic hematopoietic stem cell transplantation. In the present study, we have confirmed the sensitivity of T lymphocytes to 8-MOP treatment plus UV-A exposure as evidenced by the abrogation of the alloreactivity in mixed lymphocyte cultures as well as the inhibition of the response to phytohemagglutinin A. However, the clonogenic capacity of the bone marrow hematopoietic progenitors was inhibited with UV-A doses lower than the doses needed to inhibit T-lymphocytes alloreactivity. Moreover, long-term bone marrow cultures showed that 8-MOP plus UV-A treatment had detrimental effects on the more immature bone marrow stem cells. These data were confirmed when murine bone marrow graft was treated with 8-MOP, exposed to UV-A, then transplanted into semiallogeneic recipient mice. The treated cells could not maintain their clonogenic capacity in vivo resulting in death of all animals. Taken together, these data show that ex vivo 8-MOP plus UV-A treatment of the marrow graft cannot be used to prevent post-bone marrow transplantation alloreactivity.

Role of the thymus in radiation-induced lung damage after bone marrow transplantation.

Pneumonitis developing after total-body irradiation and bone marrow transplantation can be a serious complication of this form of therapy. In this study, the incidence of lung damage in a murine syngeneic transplant model was found to be decreased by prior removal of the thymus, indicating that thymus-derived cells, even in the absence of complicating factors such as graft-versus-host disease and opportunistic pathogens, can contribute to radiation-induced lung damage. It is suggested that the increased damage is due to a syngeneic graft-versus-host reaction mediated by a regenerating lymphoid system. If this concept is correct, new strategies can be identified that might be employed in altering the incidence of this serious transplant-related complication.

Immunomodulation in transplantation with photopheresis.

Photopheresis is a technique in which peripheral blood mononuclear cells, in the presence of a photoactivatable compound, are exposed extracorporeally to ultraviolet A light and reinfused, inducing a host autoregulatory immune response. Experimental work and ongoing clinical studies are helping to define the role of this novel, safe, and non-toxic immunomodulating technology in the field of transplantation.

[Ultraviolet rays and their dermatologic application]. / Az ultraibolya sugárzásról és börgyógyászati alkalmazásáról.

After describing the landmark results achieved so far in studying the effects of ultraviolet radiation (UVR), the authors go on to present their achievements and they point out those areas of dermatology where UVR can be applied. In connection with the letter, the authors show the latest treatment theories; indications, contraindications, treatment pattern, acute and chronic side effects. Finally, the authors give a brief summary on the interdisciplinary application of UVR.

A comparison of four ultraviolet sources to alter graft-versus-host responses.

Graft-versus-host disease (GVHD) is a major contributor to the morbidity and mortality associated with allogeneic bone marrow transplantation. Direct ultraviolet B (UVB) irradiation of bone marrow and spleen cell allografts in mice using broadband lamps is known to abolish alloreactive responses which would normally cause GVHD. Using a histoincompatible murine model, we have extended these observations by comparing the physical spectrum of four UV sources (the Philips TUV8W, TL12 and TL01, and the Spectronics XX15B) with in vitro assessment of bone marrow progenitor cell damage and suppression of lymphocyte proliferation and in vivo comparison of the effect on GVHD of the TL12 and XX15B and on the rate of engraftment with the TL12. At doses of uv found to abolish lymphocyte proliferation (2.5, 7, 12 and 1000 J m(-2) with the TUV8W, XX15B, TL12 and TL01 lamps) colony-forming unit granulocyte-macrophage (CFU-GM) proliferation was reduced to 81%, 71%, 79% and 62%, respectively. At an optimal dose found to suppress GVHD (100 J m(-2) integrated radiant energy from 200-320 nm for the TL12 and XX15B) CFU-GM proliferation showed a reduction of 98% with the XX15B and 86% with the TL12. At this radiant energy with the TL12, the rate of bone marrow engraftment was impaired with 72% marrow cellularity at 2 weeks, decreasing to 48% after 200 J m(-2). Our results with this model demonstrate that broadband UVB irradiation of bone marrow permits transplantation across a major histocompatibility barrier. Furthermore we have provided in vitro evidence that narrowband UVB or UVC might potentially be applied to this model.

[Immunopharmacological analysis of secondary postradiation immunodeficiency]. / Immunofarmakologicheskii analiz vtorichnogo postluchevogo immunodefitsita.

A model for secondary postradiation immunodeficiency of mice has been used to compare immunocorrective activities of some new immunomodulators (arbidol, cagocel, myelopid, proleukinferon and fragmine) administered at late times (2-3 months) after exposure to a nonlethal radiation dose (4.0 Gy). The highest immunocorrective effect has been shown with fragmine and proleukinferon.

[Effect of ionizing radiation on the thymus stroma of embryos and newborn mice]. / Deistvie ioniziruiushchei radiatsii na stromu timusa émbrionov i novorozhdennykh myshei.

The lobes of thymus of newborn mice irradiated on 17 day of embryonic life or on 1 day after the birth were transplanted under the renal capsule of adult mice. The recipients were thymectomized, lethally irradiated and reconstituted by syngeneic bone marrow cells treated by monoclonal anti-Thy-1-antibody and complement 1 month before the transplantation of thymus. Colonization of the thymus transplants, number and functional activity of T cells in peripheral lymphoid organs of recipients were measured 30 day after the transplantation of thymus. The colonization of the thymus transplants was decreased after irradiation of the thymus donors in doses of 6 and 8 Gy. The number of L3T4+ cells (T helpers) in the lymph nodes of the recipients and the level of the humoral immune response on thymus-dependent antigen were decreased after the exposure of the thymus donors to dose of 1 Gy or higher and the level of graft-versus-host reactivity of lymph node cells--after the dose of 2 Gy and higher. The degree of the suppression of the humoral immune response was higher when the donors of thymus were irradiated in embryonal period of development than after the birth. Thus the damage of the components of thymic microenvironment responsible for the T cell development can be arisen by relatively low doses of ionizing irradiation.

[Effect of storage duration and irradiation dose on in vitro aggregation of thrombocytes]. / Einfluss von Lagerungsdauer und Bestrahlungsdosis auf das In-vitro-Aggregationsverhalten von Thrombozyten.

We studied the influence of storage (1-5 days) and gamma irradiation (0, 25, 50, 100 Gy) on the in vitro aggregability of stored platelets. Platelet aggregation was measured using the method of Born and Breddin and the aggregating agents ADP, collagen, ristocetin and arachidonic acid. With increasing time of storage the ADP-, collagen- and ristocetin-induced platelet aggregation was significantly diminished. On the other hand, the irradiation even with 100 Gy had no additional effect.

[The biological effects in animals in relation to the accident at the Chernobyl Atomic Electric Power Station. 10. Cooperative immune reactions in different generations of mice]. / Biologicheskie éffekty u zhivotnykh v sviazi s avariei na Chernobyl'skoi AES. Soobshchenie 10. Kooperativnye immunnye reaktsii u razlichnykh pokolenii myshei.

The immune status of mice has been assessed by the whole complex of data. The permanent action of low-level radiation has been shown to suppress considerably the rate of reactions of the delayed-type hypersensitivity and "graft versus host" disease, as well as NK and specific cytolytic T-lymphocyte activity. The dynamics of accumulation and the levels of antiviral antibodies in the serum, lung and trachea extracts are virtually invariable. The resistance of experimental animals to influenza is lower than that of non-irradiated mice of the same line and age. The data obtained indicate that the immune disturbances revealed are connected not only with the alteration of lymphoid cell populations, but also with the alteration of the immune regulation mechanisms.

[The effect of ionizing radiation and immunomodulators on the development of the graft versus host reaction]. / Vliianie ioniziruiushchego izlucheniia i immunomoduliatorov na proiavlenie reaktsii "transplantat protiv khoziaina".

The reaction "transplant against host" (RTAH) was performed by subcutaneous transplantation of popliteal lymphnode lymphocytes of C57Bl/6 mice (CBA X C57Bl/6)F1 mice. gamma-Irradiation of donors with a dose of 6 Gy was shown to activate the function of T-lymphocytes, effectors in RTAH. Recipients irradiated with the same dose exhibited a drastic decrease in the ability of the organism to restrict RTAH. Decaris administered 15 min after irradiation of donors removed the postirradiation RTAH increase. In nonirradiated donors or recipients, the immunomodulators increased RTAH.

Enhancement of bone marrow allografts from nude mice into mismatched recipients by T cells void of graft-versus-host activity.

Transplantation of 8 x 10(6) C57BL/6-Nu+/Nu+ (nude) bone marrow cells into C3H/HeJ recipients after conditioning with 8 Gy of total body irradiation has resulted in a markedly higher rate of graft rejection or graft failure compared to that found in recipients of normal C57BL/6 or C57BL/6-Bg+/Bg+ (beige) T-cell-depleted bone marrow. Mixing experiments using different numbers of nude bone marrow cells with or without mature thymocytes (unagglutinated by peanut agglutinin) revealed that engraftment of allogeneic T-cell-depleted bone marrow is T-cell dependent. To ensure engraftment, a large inoculum of nude bone marrow must be supplemented with a trace number of donor T cells, whereas a small bone marrow dose from nude donors requires a much larger number of T cells for engraftment. Marked enhancement of donor type chimerism was also found when F1 thymocytes were added to nude bone marrow cells, indicating that the enhancement of bone marrow engraftment by T cells is not only mediated by alloreactivity against residual host cells but may rather be generated by growth factors, the release of which may require specific interactions between T cells and stem cells or between T cells and bone marrow stroma cells.

Alterations in T cell-derived colony-stimulating factors associated with GVH-induced immune deficiency.

Injection of parental C57BL/10 spleen cells into unirradiated immune-competent (B10 x B10.BR)F1 hosts has been demonstrated to produce a graft-vs.-host-induced immune deficiency in T cell-mediated functions, including mitogen or alloantigen stimulated proliferation or cytotoxic T cell generation. The production of T cell-derived lymphokines affecting hematopoiesis was also altered during GVH. During the first two weeks of GVH, IL-3 and particularly GM-CSF were produced spontaneously; in subsequent weeks, the spontaneous production dropped to normal or subnormal levels. CSF content in concanavalin A-stimulated splenic supernatants was reduced at weeks 1-2, and declined to less than 5% of normal levels by 3-4 weeks of GVH. This decline in CSF content was correlated with a decrease in immune function as assessed by concanavalin A-stimulated IL-2 production and by generation of cytotoxic T lymphocytes. Concurrent with the recovery of immune function during GVH weeks 8-15, mitogen-stimulated production of CSF returned to normal levels. In addition to the decrease in CSF production identified in acute suppressive GVH, CSF content in concanavalin A-stimulated splenic supernatants was also decreased in chronic stimulatory GVH, generated in the strain combination (B6 x B6bm1)F1----(B6bm1 x B6bm12)F1. This decrease in CSF production correlated with a decrease in self-restricted T helper cell function. Finally, a decrease in both immune function and CSF production capacity was observed in the acute GVH following allogeneic (minor histocompatibility loci) bone marrow transplantation into irradiated hosts.

[Prophylactic irradiation of blood components with conventional radiotherapy devices]. / Die prophylaktische Bestrahlung von Blutkomponenten mit herkömmlichen Strahlentherapiegeräten.

The irradiation of blood components is supposed to be the safest way of the graft versus host reaction prophylaxis. The radiotherapy facilities and compact irradiators for blood preparations and biological materials are used for prophylactic irradiations, practically. The radiotherapy machines allow a homogeneous dose application, but need a high organizing effort. The use of compact irradiators is less complicated but the large dose differences can be found in the target volume. There is no agreement about the extent of the prophylactic dose. For radiation biology reasons the application of prophylactic doses between 15 and 50 Gy seems to be justified. A restriction of this range in favor of higher doses can be expected, when newer experimental findings are proven by clinical observations.

Immunomodulatory action of double-stranded RNA in unirradiated and irradiated mice.

Double-stranded RNA (ds RNA) stimulates the regional graft-versus-host reaction (GVHR) in mice irradiated with 3 Gy or 5 Gy (but not 7 Gy) of gamma-rays; in control animals GVHR is not influenced. Sensitization of animals to delayed-type hypersensitivity (DTH) reaction is suppressed by ds RNA in both irradiated and unirradiated mice. In the antibody formation to sheep and blood cells (SRBC) ds RNA given before immunization inhibits the switch of IgM to IgG. When injected simultaneously with or after immunization, ds RNA markedly stimulates antibody formation. The differences in the influence of ds RNA on individual immune reactions can be explained by its different action on the regulatory mechanisms.

Experimental studies of immunologically mediated enteropathy. Development of cell mediated immunity and intestinal pathology during a graft-versus-host reaction in irradiated mice.

The intestinal component of a graft-versus-host reaction (GvHR) provides a useful experimental model to elucidate the pathogenesis of clinical enteropathies which cause villus atrophy and crypt hyperplasia and which are associated with a local immune response. One to three days after induction of GvHR in heavily irradiated (CBAxBALB/c)F1 mice, a proliferative form of enteropathy developed. Compared with controls, these mice had increased counts of jejunal intraepithelial lymphocytes and had a four-fold increase in crypt cell production rate as well as an increase in crypt length. These changes were accompanied by a marked enhancement of splenic natural killer cell activity. After day three, the crypt cell production rate fell to zero and cytotoxic T lymphocytes (CTL) which could lyse targets of host origin appeared. In parallel, mice with GvHR developed significant villus shortening and their clinical condition deteriorated. Further experiments showed that increased counts of intraepithelial lymphocytes, villus atrophy and crypt hyperplasia also occurred in grafts of fetal CBA intestine implanted under the kidney capsule of (CBAxBALB/c)F1 mice with GvHR. As these grafts are syngeneic to the injected CBA spleen cells, they should not be attacked by anti-host cytotoxic T lymphocytes. We suggest that the proliferative and destructive components of enteropathy in GvHR are caused by lymphokines released by an anti-host delayed type hypersensitivity reaction.

Roles of mucosal mast cells in intestinal cell-mediated immunity.

Mucosal mast cells in rats with GvHR have been studied by cell counts, tissue levels of the specific protease RMCPII, and, as an index of MMC activation, serum RMCPII. In semi-allogeneic GvHR without host irradiation, GvHR produced modest increases in these three indices. In contrast, irradiation profoundly depleted MMC even though enteropathy was more severe than in non-irradiated hosts. We suggest that enteropathy is not dependent on the presence of MMC. In rats given cyclosporin A, lesions of GvHR were mild and numbers of MMC were low.

Influence of MHC on thymus repopulation following intrathymic transfer of mouse T-cell precursors.

T-cell precursors (pre-T cells) traditionally have been detected by their ability to repopulate the thymus of heavily irradiated mice following intravenous injection. Recently, an assay system involving the direct injection of pre-T cells into the thymus of sublethally irradiated animals has been described. Here we report the results of experiments designed to evaluate the ability of bone marrow cells to produce thymic repopulation following intrathymic injection in a wide range of donor-host strain combinations. Irradiated (600 R) mice were injected intrathymically with 2 X 10(6) bone marrow cells which differed from the recipient with respect to their Thy-1 allotype and the percentage of thymus cells expressing either donor- or recipient-type Thy-1 was determined 9 to 23 days after injection. The results of these experiments showed that thymocytes expressing the Thy-1 allotype derived from the donor marrow were only detected when the donor and host were matched at MHC. By contrast, thymic repopulation by MHC-mismatched donor marrow cells could readily be observed when these cells were given intravenously.