scholarly journals AN ANALYSIS OF GRAFT-VERSUS-HOST DISEASE IN SYRIAN HAMSTERS

1970 ◽  
Vol 132 (1) ◽  
pp. 181-197 ◽  
Author(s):  
J. Wayne Streilein ◽  
R. E. Billingham
Keyword(s):  
Bone Marrow ◽  
Graft Versus Host Disease ◽  
Lymphoid Cells ◽  
Transfer Reactions ◽  
F1 Hybrids ◽  
F1 Hybrid ◽  
Graft Versus Host ◽  
Immune Lymphocyte ◽  
Donor Cells ◽  
Lymphocyte Transfer

The epidermolytic syndrome that can be obtained at will in F1 hybrid hamsters by the cutaneous inoculation of adequate doses of parental strain lymphoid cells has been investigated to determine whether the cutaneous lesions are due to an autoimmune process arising from the severe, initial GVH reactions in the skin. It was amply demonstrated that inoculation of donor cells into the skin was of crucial importance to the development of epidermolysis. Parental strain lymphoid cells in similar doses delivered by any other route into normal F1 hybrids failed absolutely to incite the acute syndrome. If "immune lymphocyte transfer" reactions incited by donor cells in the host's skin were surgically removed at timed intervals after inoculation, only complete excision within 24 hr prevented the appearance of epidermolysis in F1 hybrid hosts, indicating that inoculated donor cells must remain within the confines of the skin for approximately 24 hr in order to evoke the disease, persistence for longer periods of time being unnecessary for the subsequent course of the disease. However, reconstitution experiments involving the intramuscular inoculation of suspensions containing mixtures of donor cells and host lymphoid cells, in the presence or absence of epidermal cells, unequivocally indicated that no intimate exposure of lymphoid cells to putative skin-specific antigens was essential. Similarly, the elicitation of generalized epidermolysis in F1 hybrids irradiated with 300 r and then inoculated intravenously with donor cells casts further doubt on the pathogenic importance of the skin as a source of tissue-specific antigen. The results of subsequent experiments indicated that host leukocytes, rather than parenchymal cells of the dermis or the epidermis, were important contributors of the transplantation antigenic stimulus. Moreover, a series of experiments, using (CB x MHA)F1 hybrid hosts that had been lethally irradiated and reconstituted with bone marrow cells from ALS-treated MHA donors, indicated that from 6 to 10 wk after reconstitution—when direct and immune lymphocyte transfer reactions showed a virtual absence of native F1 leukocytes from the circulation—donor cells obtained from specifically sensitized MHA donors were completely ineffective in inducing epidermolysis, while equivalent lymphoid cell inocula derived from CB donors evoked the cutaneous disease irrespective of the time elapsed since reconstitution. To explain these findings it is postulated that in hamsters, the primary targets in graft-versus-host disease incited by the intracutaneous inoculation of donor cells are leukocytes originating in bone marrow or lymph node, or both.

scholarly journals ANALYSIS OF GRAFT-VERSUS-HOST DISEASE IN SYRIAN HAMSTERS

1972 ◽  
Vol 135 (3) ◽  
pp. 567-578 ◽  
Author(s):  
J. Wayne Streilein
Keyword(s):  
Graft Versus Host Disease ◽  
Lymphoid Cells ◽  
Antigenic Determinants ◽  
F1 Hybrid ◽  
Host Disease ◽  
Syrian Hamsters ◽  
Graft Versus Host ◽  
Refractory State ◽  
Lymphocyte Transfer ◽  
Additional Support

The so-called refractory state, one sequela of acute graft-versus-host disease, has been studied in adult (CB x MHA)F1 hybrid Syrian hamsters inoculated with sublethal numbers of MHA-anti-CB lymphoid cells. Intracutaneous challenge of these animals with 200 million MHA-anti-CB lymphoid cells after the acute syndrome subsided failed to evoke epidermal necrolysis, whereas a similar challenge administered to normal F1 recipients invariably resulted in lethal epidermolysis. Moreover, the gradual attrition of lymphatic tissues in these hosts and their fading capacity to display adequately immune lymphocyte transfer reactions in the skin coincided with increasing evidence of host refractoriness, suggesting a causal interrelationship. It was possible to circumvent refractoriness by challenging these animals intracutaneously with MHA-anti-CB cells if: (a) the hosts had been lethally irradiated and reconstituted with F1 hematopoietic cells, or (b) the intracutaneous inocula contained admixed F1 lymphoid cells. This evidence provides additional support for the hypothesis that in GVH disease donor lymphocytes attack primarily host lymphoid cells bearing offending homologous antigens. The GVH process can continue so long as these lymphocyte-bound antigens persist within the host, and will abate only as the aggregate host lymphatic mass is effectively destroyed (hamsters) or its antigenic determinants are masked by isoantibodies (rats, mice, man?). At this point, insufficient target tissues remain for rechallenge to incite significant recrudescence of the disease.

scholarly journals Immune responses to major histocompatibility complex homozygous lymphoid cells in murine F1 hybrid recipients: implications for transfusion-associated graft-versus-host disease

Blood ◽  
1995 ◽  
Vol 86 (8) ◽  
pp. 3090-3096 ◽  
Author(s):  
LD Fast ◽  
CR Valeri ◽  
JP Crowley
Keyword(s):  
Natural Killer Cells ◽  
Immune Responses ◽  
Natural Killer ◽  
Graft Versus Host Disease ◽  
Lymphoid Cells ◽  
Killer Cells ◽  
F1 Hybrid ◽  
Host Disease ◽  
Graft Versus Host ◽  
Donor Cells

Graft-versus-host disease (GVHD) is currently encountered after bone marrow transplantation and transfusion. GVHD associated with transfusion (TA-GVHD) in apparently immunocompetent recipients has been recently reported with increasing frequency. A consistent finding in many of these cases is that the recipient received blood from a donor homozygous for one of the recipient's HLA haplotypes. However, the observed frequency of TA-GVHD is much lower than the estimated probability of this donor/recipient combination. The potential role of recipient immune responses in controlling TA-GVHD was investigated using an analogous murine model in which GVHD is induced by the injection of parental lymphoid cells into unirradiated F1 hybrid recipients. The effect of various immune manipulations of the recipient of GVHD induction was assessed by determining the number of donor lymphoid cells required to induce GVHD responses. Whereas depletion of recipient CD4+ cells increased the number of donor cells needed to induce GVHD, depletion of recipient CD8+ and natural killer cells resulted in fewer donor cells being needed to induce a GVHD response. These studies suggest a central role for functioning recipient CD8 and natural killer cells in the down-regulation of TA-GVHD development in recipients.

scholarly journals Immune responses to major histocompatibility complex homozygous lymphoid cells in murine F1 hybrid recipients: implications for transfusion-associated graft-versus-host disease

Blood ◽  
1995 ◽  
Vol 86 (8) ◽  
pp. 3090-3096 ◽  
Author(s):  
LD Fast ◽  
CR Valeri ◽  
JP Crowley
Keyword(s):  
Natural Killer Cells ◽  
Immune Responses ◽  
Natural Killer ◽  
Graft Versus Host Disease ◽  
Lymphoid Cells ◽  
Killer Cells ◽  
F1 Hybrid ◽  
Host Disease ◽  
Graft Versus Host ◽  
Donor Cells

Abstract Graft-versus-host disease (GVHD) is currently encountered after bone marrow transplantation and transfusion. GVHD associated with transfusion (TA-GVHD) in apparently immunocompetent recipients has been recently reported with increasing frequency. A consistent finding in many of these cases is that the recipient received blood from a donor homozygous for one of the recipient's HLA haplotypes. However, the observed frequency of TA-GVHD is much lower than the estimated probability of this donor/recipient combination. The potential role of recipient immune responses in controlling TA-GVHD was investigated using an analogous murine model in which GVHD is induced by the injection of parental lymphoid cells into unirradiated F1 hybrid recipients. The effect of various immune manipulations of the recipient of GVHD induction was assessed by determining the number of donor lymphoid cells required to induce GVHD responses. Whereas depletion of recipient CD4+ cells increased the number of donor cells needed to induce GVHD, depletion of recipient CD8+ and natural killer cells resulted in fewer donor cells being needed to induce a GVHD response. These studies suggest a central role for functioning recipient CD8 and natural killer cells in the down-regulation of TA-GVHD development in recipients.

scholarly journals STUDIES ON NORMAL AND IMMUNE LYMPHOCYTE TRANSFER REACTIONS IN GUINEA PIGS, WITH SPECIAL REFERENCE TO THE CELLULAR CONTRIBUTION OF THE HOST

1972 ◽  
Vol 136 (6) ◽  
pp. 1545-1563 ◽  
Author(s):  
Siraik Zakarian ◽  
R. E. Billingham
Keyword(s):  
Guinea Pigs ◽  
Significant Proportion ◽  
Intradermal Injection ◽  
Lymphoid Cells ◽  
Delayed Hypersensitivity ◽  
F1 Hybrids ◽  
Genetic Constitution ◽  
F1 Hybrid ◽  
Immune Lymphocyte ◽  
Lymphocyte Transfer

Using guinea pigs of strains 2 and 13 and their F1 hybrids as experimental subjects, various lines of evidence have been obtained that in this species, as in all others tested, the only significant cellular antigens with which donor lymphocytes engage when normal and immune lymphocyte reactions are incited are radiosensitive leukocytes. Constitutive cells of the skin are unimportant. (a) The intensities of these reactions in irradiated subjects are dependent upon the peripheral leukocyte concentration. When this falls below a certain threshold no reactions are incitable. (b) Highly leukopenic animals are capable of developing immune lymphocyte transfer (ILT) reactions if normal lymphoid cells of their own genetic constitution are mixed with the putative attacking donor cells, as "supplementing antigen," before inoculation. (c) Radiation-chimeric strain 13 animals having F1 hybrid leukocytes in their bloodstream give typical ILT reactions when challenged intradermally with strain 13 anti-2 node cells. Exposure of strain 2 animals to 600 R does not prevent their becoming actively immunized if, 24 hr later, they are injected intradermally with strain 13 lymphocytes. However, this sensitization, revealed by the host's capacity to give delayed hypersensitivity reactions, wanes as leukopenia progresses. On the basis of this and other findings it is argued that the flare-up stage of the NLT reaction in preirradiated hosts is mainly an expression of host sensitivity against the transferred alien cells. Two unexpected observations have been made in the course of this study: (a) F1 hybrid animals developed what appeared to be a strong delayed hypersensitivity after intradermal inoculation with parental strain lymphoid cells or antigenic extracts prepared from them. (b) If strain 13 guinea pigs which had been sensitized against strain 2 tissue antigens by intradermal injection of lymphocytes 7 days beforehand were inoculated intravenously with strain 2 antigenic extract a significant proportion of the animals developed severe delayed necrotizing reactions, recall flares, at some or all of the healed skin inoculation sites.

scholarly journals Brief Report: Graft-Versus-Host Reaction in F1 Hybrid Mice Injected with Pre-Immunized Parental Thymus Cells

Blood ◽  
1964 ◽  
Vol 24 (6) ◽  
pp. 770-774 ◽  
Author(s):  
LUCIANO FIORE-DONATI ◽  
LUIGI CHIECO-BIANCHI ◽  
GIUSEPPE DE BENEDICTIS ◽  
GIUSEPPE TRIDENTE
Keyword(s):  
Lymphoid Cells ◽  
The Other ◽  
F1 Hybrids ◽  
Graft Versus Host Reaction ◽  
Host Reaction ◽  
F1 Hybrid ◽  
Graft Versus Host ◽  
Immunologic Activity ◽  
Thymus Cells ◽  
Hybrid Mice

Abstract Dissociated thymus cells are capable of initiating graft-versus-host reaction in (C3Hf/Gs x DBA/2)F1 hybrids only when derived from parental donors previously sensitized against the antigens of the other parental strain. The lower immunologic activity of thymus cells as compared with other lymphoid cells is presumably due to quantitative rather than qualitative differences in immunologically competent cells.

Total Body Irradiation Creates a Proinflammatory Milieu That Is Required for Minor, but Not Major, Mismatch Graft-Versus-Host-Disease.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3736-3736
Author(s):  
Sam C Nalle ◽  
Peter A Savage ◽  
Jerrold R Turner
Keyword(s):  
Bone Marrow ◽  
Weight Loss ◽  
T Cells ◽  
Graft Versus Host Disease ◽  
Clinical Symptoms ◽  
Conditioning Regimen ◽  
Target Organ ◽  
Host Disease ◽  
Graft Versus Host ◽  
Donor Cells

Abstract Abstract 3736 Background Graft-versus-host disease (GVHD) is a potentially fatal complication following allogeneic bone marrow transplantation (BMT). GVHD is characterized by three phases: (1) recipient tissue injury mediated by the conditioning regimen of irradiation and/or chemotherapy; (2) donor cell priming and activation; and (3) effector destruction of target tissue such as the intestine, liver, skin, and lung. There is some evidence to suggest that the second and third phases are dependent on the first, however, this has not been rigorously tested. Therefore, we developed major and minor mismatch models of GVHD and used immunodeficient recipients that readily accept allografts to analyze the requirement of irradiation conditioning on GVHD initiation and development. Experimental Design Wild-type (WT) B6 (H-2b) recipients received major mismatch (Balb/c, H-2d), minor mismatch (129, H-2b), or syngeneic (B6) BMTs. Recipients were lethally irradiated, and 24 hours later received an intravenous infusion of 5 × 106 bone marrow cells and 30 × 106 splenocytes, as a source of mature T cells. In adoptive transfer (AT) experiments, B6 Rag1−/− or B6 Rag2−/−/Pfp−/− (perforin deficient) recipients received 30 × 106 splenocytes. Data are represented as mean ± SEM. Results In lethally irradiated WT recipients, Balb/c→B6 caused severe GVHD that was fatal in all recipients by 24 days after BMT. 129→B6 led to a milder GVHD, where 50% of recipients survived to 35 days after BMT, and a few survived long-term (>100 days). Both major and minor mismatch GVHD were characterized by 15–25% weight loss, clinical symptoms including decreased activity, hunched posture, ruffled fur, and hair loss, and target organ histopathology. To test the requirement of irradiation conditioning in GVHD, we transferred Balb/c splenocytes into unconditioned B6 Rag1−/− recipients. No signs of GVHD developed. However, donor T cells were virtually undetectable 5 weeks after AT, indicating graft rejection. To test if this was due to recipient natural killer (NK) cells, a major mismatch AT was performed into B6 Rag2−/−/Pfp−/− recipients, which lack fully functional NKs. Balb/c→B6 Rag2−/−/Pfp−/− resulted in GVHD, including 10–15% weight loss, clinical symptoms, and target organ histopathology, although the disease was not as severe as that following lethal irradiation of WT recipients, consistent with a facilitative role for conditioning in disease progression. In contrast to the above, a 129 splenocyte AT did not cause GVHD in Rag1−/− or Rag2−/−/Pfp−/− recipients, despite donor T cell engraftment. This suggested that conditioning was required for minor mismatch GVHD. To test this, we sublethally irradiated Rag1−/− recipients prior to 129 AT. This resulted in GVHD, with 10–15% weight loss, clinical symptoms, and histopathology. At day 7 after AT, serum IFNγ, TNF, and IL-6 were significantly greater in mice that received irradiation and AT (compared to AT alone, p<0.05). Donor cells within spleens of mice that received irradiation and AT had a reduced fraction of Foxp3+/CD4+ (9.5%±2.3) compared to AT alone (16.8%±1.6, p=0.06), and increased intracellular CD8+ IFNγ expression (%IFNγ+:47.7±2.4 vs. 41.6±1.8, p<0.05; MFI:15722±2003 vs. MFI:8025±319, p<0.05). To determine whether more alloreactive donor cells were primed after irradiation, an in vivo killing assay was performed with recipient-specific targets. Combined irradiation and AT resulted in 66.3±13.5% killing efficiency while AT only had an 18.9±11.7% killing efficiency. Conclusions We conclude that irradiation conditioning is required for minor, but not major mismatch GVHD. The conditioning regimen creates the necessary proinflammatory milieu to prime sufficient numbers of alloreactive cells for GVHD. While this milieu can enhance development of major mismatch GVHD, it is not required for development of disease. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Selective targeting of the LIGHT-HVEM costimulatory system for the treatment of graft-versus-host disease

Blood ◽  
2006 ◽  
Vol 109 (9) ◽  
pp. 4097-4104 ◽  
Author(s):  
Yanhui Xu ◽  
Andrew S. Flies ◽  
Dallas B. Flies ◽  
Gefeng Zhu ◽  
Sudarshan Anand ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Graft Versus Host Disease ◽  
Allogeneic Bone Marrow Transplantation ◽  
Allogeneic Bone Marrow ◽  
Proliferative Potential ◽  
Allogeneic Bone ◽  
Host Disease ◽  
Graft Versus Host ◽  
Donor Cells

Abstract Decoy lymphotoxin β receptor (LTβR) has potent immune inhibitory activities and thus represents a promising biologic for the treatment of inflammation, autoimmune diseases, and graft-versus-host disease (GVHD). As this reagent interrupts multiple molecular interactions, including LTβ-LTβR and LIGHT-HVEM/LTβR, underlying molecular mechanisms have yet to be fully understood. In this study, we demonstrate that blockade of the LIGHT-HVEM pathway is sufficient to induce amelioration of GVHD in mouse models. Anti–host cytotoxic T lymphocyte (CTL) activity following in vivo transfer of allogeneic lymphocytes was completely abrogated when LIGHT- or HVEM-deficient (KO) T cells were used as donor cells. Accordingly, survival of the recipient mice following the transfer of allogeneic bone marrow cells plus LIGHT-KO or HVEM-KO T cells was significantly prolonged. In the absence of LIGHT-HVEM costimulation, alloreactive donor T cells undergo vigorous apoptosis while their proliferative potential remains intact. Furthermore, we prepared a neutralizing monoclonal antibody (mAb) specific to HVEM and showed that administration of anti–HVEM mAb profoundly ameliorated GVHD and led to complete hematopoietic chimerism with donor cells. Collectively, our results demonstrate an indispensable role of LIGHT-HVEM costimulation in the pathogenesis of GVHD and illustrate a novel target for selective immunotherapy in allogeneic bone marrow transplantation.

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