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PubMed1992

CD3+ and CD4+ cells adoptively transfer experimental hypersensitivity pneumonitis.

To characterize the cells responsible for transfer of adoptive murine experimental hypersensitivity pneumonitis (EHP), we depleted Micropolyspora faeni (M. faeni)-sensitized C3H/HeJ spleen cell (SC) cultures of CD3+, CD4+, or CD8+ cells before administration to recipients. We determined the length of time sensitization persists, the ability of cultured lung-associated lymph node (LALN) cells to transfer EHP, and the ability of cultured SC from animals subjected to two, four, or eight weekly intratracheal challenges of M. faeni to transfer EHP. The extent of pulmonary inflammatory response after challenge with intratracheal M. faeni was used to determine adoptive transfer. Depletion reduced the proportion of CD3+ cells from 21 to 1%, CD4+ cells from 15 to 3%, and CD8+ cells from 7 to 1% in the cultured SC population. The proportion of B cells exhibited reciprocal changes. Cultured SC could transfer EHP. Depletion of CD3+ and CD4+, but not CD8+ cells, ablated or diminished the capacity to transfer EHP. Sensitized cells persisted in recipients for at least 8 wk. Cultured LALN cells could transfer EHP. Recipients of cultured SC from 4- and 8-wk donors exhibited less extensive pulmonary abnormalities than recipients of cultured SC from 2-wk donors. The proportion of CD3+, CD4+, CD8+, B cells, and macrophages was the same in cultured cells from 2-, 4-, and 8-wk donors. We conclude that the active cells in SC cultures are CD3+, CD4+, and CD8- T cells, and there are differences in the ability of cultured cells to adoptively transfer EHP that are dependent on the nature of the donor but not on the phenotype of the cell population.

Alveolitis, Extrinsic Allergic↗
PubMed1973

Cell interactions between histoincompatible T and B lymphocytes. I. Allogeneic effect by irradiated host T cells on adoptively transferred histoincompatible B lymphocytes.

The adoptive transfer of 2,4-dinitrophenyl(DNP)-keyhole limpet hemocyanin(KLH)-primed lymphocytes into a heavily irradiated allogeneic recipient permits the development of a secondary anti-DNP antibody response to DNP-bovine gamma globulin(BGG) whether or not the irradiated allogeneic host possesses BGG-specific helper T cells. This "allogeneic effect" has been demonstrated to result from the capacity of residual, apparently radioresistant, T cells in the irradiated host to exert an active effect on the transferred histoincompatible B lymphocytes. This conclusion derives from two corroborative experiments. In the first, an allogeneic effect was shown to occur on DNP-primed F(1) spleen cells that had been adoptively transferred to irradiated parental recipients; the second experiment demonstrated the development of an allogeneic effect on anti-theta-treated, DNP-specific donor cells transferred to irradiated allogeneic hosts. These results emphasize the extreme caution required in designing and interpreting experiments that may involve adoptive cell transfers into histoincompatible hosts, and illustrate why such models are unsuitable for investigation of the question of physiologic cooperative interactions between T and B lymphocytes. Suitable approaches are described in the accompanying paper.

Animals↗
PubMed1982

The role of the major histocompatibility complex in the adoptive transfer of ectromelia virus meningitis.

Adoptive transfer of ectromelia virus meningitis was most efficient when donor-immune spleen cells and recipients were compatible in the K region of the H-2 gene complex. Weak responses could be obtained with H-2D region compatibility, but none occurred with H-2I region compatibility. Spleen cells used in adoptive transfers and cells found in cerebrospinal fluid from infected mice were found to have identical H-2-imposed restriction in their in vitro cytotoxic activity. This suggests a significant role for the major histocompatibility complex in the generation of virus-specific T lymphocytes and the recognition of virus-infected tissue in the central nervous system by these cells.

Animals↗
PubMed2000

Maintenance of immune memory to the hepatitis B envelope protein following adoptive transfer of immunity in bone marrow transplant recipients.

Adoptive transfer of immunity against hepatitis B surface antigen (HBsAg) has been documented in mice and humans. In the present study, we report long-term follow-up of antibodies to HBsAg in humans who received allogeneic bone marrow transplantation (BMT) from donors immunized with HBsAg. BM donors were immunized with recombinant HBsAg. BM or PB cells were transplanted to HLA matched recipients. Recipients were followed for anti-HBs seroconversion. Control groups included non-immunized or rHBsAg immunized healthy adults as well as individuals that had had hepatitis B and recovered spontaneously. PBLs were stimulated in vitro with rHBsAg and stimulation was expressed as stimulation index. Adoptive transfer of immunity to HBsAg was initially documented in 12 recipients of BM from anti-HBc+/anti-HBs+ donors. An almost 4 year follow-up showed detectable protective anti-HBs levels (>10 mIU/ml) in 50% of patients. Immunity to HBV was also documented in 22/35 BMT recipients (62%), who received their bone marrow from actively immunized donors. In 7/9 of these BMT recipients, anti-HBs antibodies levels were documented 25 months following BMT. In 6/8 (75%) of patients who received only PBLs from HBV immune donors, adoptive transfer of immunity to HBV, and seroconversion to HBsAg+, were documented within 2 months of i.v. injection. Evidence for specific cellular immune response with increased SIs was documented for healthy vaccinees, and BMT recipients, and in none of the healthy non-vaccinated controls. These results suggest that adoptive transfer of immunity to HBV is a useful method for providing long-lasting protection for BM recipients.

Adult↗
PubMed1985

T-cell involvement in adoptive transfer of line 10 tumor immunity in strain 2 guinea pigs.

Several aspects of adoptive transfer of tumor immunity were studied in the line 10 hepatocarcinoma in the syngeneic Sewall-Wright strain 2 guinea pig. In particular, the need for cooperation between donor and recipient T-cells was investigated. Donor immune spleen cells remained immunologically capable of inducing tumor rejection for at least 160 days after adoptive transfer. Irradiated (1,000 rad) or mitomycin-treated immune spleen cells lacked tumor-rejection activity, which is indicative of the necessity for in vivo proliferation after adoptive transfer of immunity. Furthermore, adoptive transfer of tumor immunity was abrogated after treatment of the line 10 immune spleen cells with rabbit anti-guinea pig-thymocyte serum (ATS) plus complement. The role of recipient T-cells was investigated in strain 2 guinea pigs which were T-cell depleted by thymectomy, irradiation, and bone marrow reconstitution (T-XBM animals). Severe suppression of T-cell activity was present at 2 and 6 weeks after irradiation and bone marrow reconstitution. At 10 weeks nonspecific T-cell activity was partially restored. The induction of antigen-specific responses, measured by delayed-type hypersensitivity skin testing in vivo and antigenic stimulation in vitro, was suppressed at 2 weeks after irradiation and bone marrow reconstitution. Additional in vivo treatment of T-XBM animals with a rabbit ATS improved the T-cell depletion only moderately. Tumor growth and tumor rejection after adoptive transfer of immunity were equal in normal and T-cell-deprived recipient animals, thus indicating that recipient T-cells are not needed for tumor rejection after adoptive transfer of line 10 tumor immunity.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2005

Optimum in vitro expansion of human antigen-specific CD8 T cells for adoptive transfer therapy.

Increasing evidence suggests that adoptive transfer of antigen-specific CD8(+) T cells could represent an effective strategy in the fight against chronic viral infections and malignancies such as melanoma. None the less, a major limitation in the implementation of such therapy resides in the difficulties associated with achieving rapid and efficient expansion of functional T cells in culture necessary to obtain the large numbers required for intravenous infusion. Recently, the critical role of the cytokines interleukin (IL)-2, IL-7 and IL-15 in driving T cell proliferation has been emphasized, thus suggesting their use in the optimization of expansion protocols. We have used major histocompatibility complex (MHC) class I/peptide multimers to monitor the expansion of antigen-specific CD8 T lymphocytes from whole blood, exploring the effect of antigenic peptide dose, IL-2, IL-7 and IL-15 concentrations on the magnitude and functional characteristics of the antigen-specific CD8(+) T cells generated. We show here that significant expansions of antigen-specific T cells, up to 50% of the CD8(+) T cell population, can be obtained after a single round of antigen/cytokine (IL-2 or IL-15) stimulation, and that these cells display good cytolytic and interferon (IFN)-gamma secretion capabilities. Our results provide an important basis for the rapid in vitro expansion of autologous T cells from the circulating lymphocyte pool using a simple procedure, which is necessary for the development of adoptive transfer therapies.

Adoptive Transfer↗
PubMedDate not supplied

Accumulation in tumor tissue of adoptively transferred T cells: A comparison between intravenous and intraperitoneal injection.

Accumulation of T cells at the tumor is essential in cancer immunotherapy based on adoptive transfer of tumor-specific T cells. To gain further insight into the accumulation process and to evaluate the effect of using different routes of cell transfer, we investigated the accumulation of ovalbumin-specific CD8+ T cells (OT-I) injected either intravenously (IV) or intraperitoneally (IP) into mice carrying a subcutaneous tumor of the ovalbumin-expressing melanoma cell line B16-OVA. Maximal accumulation of the adoptively transferred cells in tumor tissue was observed 5 days after injection, irrespective of the injection route. The route of injection affected neither the total number of adoptively transferred cells found in tumor tissue nor the kinetics of this accumulation. In the spleen, however, the accumulation of adoptively transferred cells was clearly dependent on the injection route. IP injections resulted in a large number of adoptively transferred cells in the spleen on all days analyzed. In comparison, IV injection resulted in significantly fewer adoptively transferred cells in the spleen, and this number decreased over time. The route of injection affected neither the activation status of the adoptively transferred T cells that accumulated at the tumor site, nor the ability of these cells to control tumor growth. Two cell populations, SIINFEKL-tetramer(Low)(Tet(Low))CD69+ CD25+ and Tet(high)CD69- CD25-, were present in tumor samples, whereas only Tet(High)CD69- CD25- cells accumulated in the spleen. In tumors, IV injection resulted in a higher fraction of adoptively transferred cells with an activated phenotype (Tet(Low)CD69+ CD25+) compared with IP injection.

Adoptive Transfer↗
PubMed2005

Toward improved immunocompetence of adoptively transferred CD8+ T cells.

Adoptive transfer of autologous or allogenic T cells to patients is being used with increased frequency as a therapy for infectious diseases and cancer. However, many questions remain with regard to defining optimized procedures for preparation and selection of T cell populations for transfer. In a new study in this issue of the JCI, Gattinoni and colleagues used a TCR transgenic mouse model to examine in vitro-generated tumor antigen-specific CD8+ T cells at various stages of differentiation for their efficacy in adoptive immunotherapy against transplantable melanoma. The results confirm that CD8+ T cells progressively lose immunocompetence with prolonged in vitro cultivation and suggest that effector CD8+ T cells alone may be considerably less potent at protecting hosts with advanced tumors than are less differentiated T cells.

Animals↗
PubMed1986

Inhibition and augmentation of lymphoma metastasis by adoptively transferred peritoneal macrophages in hamster.

The effect of adoptively transferred peritoneal exudate cells on the metastasis of hamster lymphoma was studied. Metastatic spread occurring after the surgical removal of a primary tumor was considerably inhibited by the adoptive transfer of the peritoneal exudate cells (PEC) stimulated by immunostimulants, using a streptococcal preparation (OK-432) or a purified beta (1-3) glucan (SPG). However, the inhibitory effect on metastasis was abrogated by the in vitro treatment of the peritoneal adherent cells with silica. PEC stimulated with lymphokines in vitro was also effective in inhibiting metastasis. However, the adoptive transfer of peritoneal adherent cells treated in vitro with 12-O-tetradecanoylphorbol acetate (TPA) in vitro, augmented metastatic spread in tumor-bearing hamsters which usually exhibit concomitant immunity. The relation of the state of the functional activity of macrophages to metastasis is discussed.

Animals↗
PubMed1992

Restoration of viral immunity in immunodeficient humans by the adoptive transfer of T cell clones.

The adoptive transfer of antigen-specific T cells to establish immunity is an effective therapy for viral infections and tumors in animal models. The application of this approach to human disease would require the isolation and in vitro expansion of human antigen-specific T cells and evidence that such T cells persist and function in vivo after transfer. Cytomegalovirus-specific CD8+ cytotoxic T cell (CTL) clones could be isolated from bone marrow donors, propagated in vitro, and adoptively transferred to immunodeficient bone marrow transplant recipients. No toxicity developed and the clones provided persistent reconstitution of CD8+ cytomegalovirus-specific CTL responses.

Antigens, Differentiation, T-Lymphocyte↗
PubMed1991

In vivo proliferation of adoptively transferred tumor-infiltrating lymphocytes in mice.

The adoptive transfer of tumor-infiltrating lymphocytes (TILs) in conjunction with interleukin-2 (IL-2) administration can mediate a reduction in established pulmonary and hepatic metastases of a variety of murine tumors as well as in patients with metastatic melanoma. To characterize further the fate of adoptively transferred TILs, the uptake of the thymidine analog 5-[125I]iodo-2-deoxyuridine ([125I]UdR) into the DNA of dividing cells was used to study the in vivo proliferation and migration patterns of transferred TILs in C57BL/6N mice. Animals received 500 rad of total body irradiation prior to cell transfer to separate incorporation of radiolabel into endogenous lymphoid cells from that into transferred TILs. Mice were subsequently treated with i.v. injections of TILs or no cells followed by i.p. injections of Hanks' balanced salt solution or IL-2. At various time points, mice received [125I]UdR, and 20 h later tissues were removed and counted on a gamma analyzer. A proliferation index (PI) was calculated by dividing the mean cpm of organs of experimentally treated mice by the mean cpm of organs of control mice. Animals receiving TILs alone demonstrated small increases in [125I]UdR in the lungs, liver, and spleen of saline-treated controls (PI = 1.4, 1.6, and 1.7, respectively, on day 4), while animals treated with 50,000 U of IL-2 alone showed greater increases in the lungs, liver, kidneys, and spleen (PI = 3.9, 6.1, 3.3, and 15.8). Mice receiving TILs plus IL-2 demonstrated the highest levels of radiolabel incorporation in the same organs (PI = 10.5, 19.4, 10.2, and 22.4). Over a period of 10 days, TIL plus IL-2 treated animals continued to incorporate significantly greater amounts of [125I]UdR for as long as high-dose IL-2 was administered. Animals treated with TILs demonstrated increased incorporation of radiolabel with increasing doses of IL-2. Injection of irradiated TILs did not result in an increased uptake of [125I]UdR into these tissues, thus confirming that TIL proliferation is responsible for the radiolabel uptake in animals receiving TILs alone or TILs plus IL-2. Additionally, fluorescein-labeled anti-Thy-1.1 antibody identified proliferating TILs derived from congenic B6.PL Thy 1a/CY (Thy-1.1) animals in the lungs, spleen, and liver of recipient C57BL/6N (Thy 1.2) mice. In summary, we have demonstrated that adoptively transferred TILs distribute widely after i.v. injection and can proliferate in various tissues especially under the influence of exogenous IL-2.

Animals↗
PubMed1992

Sympathectomy augments adoptively transferred experimental allergic encephalomyelitis.

Adoptively transferred experimental allergic encephalomyelitis (EAE) was significantly augmented in Lewis rats with ablated sympathetic nervous system. Sympathectomy was obtained by treatment of newborn rats with 6-hydroxydopamine. Sham-injected rats were used as a control. EAE was elicited in 7-8-week-old donor Lewis rats by immunization with a suspension of guinea pig (GP) brain and spinal cord in complete Freund's adjuvant. Successful transfer of EAE was accomplished with 50 x 10(6) lymph node cells (LNC)/rat, incubated for 72 h with GP myelin basic protein. LNC were obtained from draining lymph nodes, 9 days after immunization for EAE. The severity of passively transferred EAE was significantly augmented when donor LNC obtained from normal Lewis rats immunized for EAE were injected into sympathectomized rats as compared to sham-injected rats. When LNC were obtained from sympathectomized or sham-injected donors, the disease was significantly more severe in recipients of cells from sympathectomized animals. The severity of histological lesions in the brain and spinal cord was greater in rats with passively transferred EAE which received LNC from sympathectomized donors.

Animals↗
PubMed1997

Th1 CD4+ cells adoptively transfer experimental hypersensitivity pneumonitis.

Cultured cells from Micropolyspora faeni-sensitized donors can adoptively transfer murine experimental hypersensitivity pneumonitis (EHP). To determine whether the CD4+ cells responsible for transfer have characteristics of Th1 or Th2 cells, we established cell lines from lung-associated lymph nodes of M. faeni-sensitized C3H/HeJ mice by culturing with antigen and either IFN-gamma, IL2, and anti-IL4, or IL4. Cell lines were stimulated regularly with antigen, fresh antigen-presenting cells, and the cytokine/anti-cytokine antibody cocktail. At various times after initiation of culture, cells were injected intravenously into recipients, which were then challenged intratracheally with M. faeni and sacrificed and the extent of pulmonary inflammatory response was determined. IFN-gamma, IL4, and IL10 levels were determined in supernatants of cell cultures stimulated with M. faeni to characterize the cell lines as Th1 (IFN-gamma, but low IL4 and IL10 secretion) or Th2 (IL4 and IL10, but low IFN-gamma secretion). Cell lines were differentiated into either Th1 (IFN-gamma = 310 +/- 45 U/ml, IL4 = 0.10 +/- 0.1 U/ml, IL10 = 1750 +/- 75 pg/ ml, >99% CD4+) cell lines by Day 16 of culture or Th2 cell lines (IFN-gamma = 1.8 +/- 1.0 U/ml, IL4 = 830 +/- 388 U/ml, IL10 = 51,700 +/- 10,900 pg/ml, >96% CD4+) by Day 30. Th1 cell lines were able to adoptively transfer EHP whereas Th2 cell lines were unable to adoptively transfer EHP. The ability to transfer EHP was directly related to the amount of IFN-gamma and inversely to the amount of IL4 secreted by antigen-stimulated cells. We conclude that it is possible to produce CD4+ cell lines with either Th1 or Th2 characteristics from lung-associated lymph nodes of mice exposed to M. faeni and that only Th1 CD4+ cell lines can adoptively transfer EHP.

Adoptive Transfer↗
PubMed1997

Suppression of human hepatoma in mice through adoptive transfer of immunity to the hepatitis B surface antigen.

BACKGROUND/AIMS: Adoptive transfer of immunity against hepatitis B surface antigen (HBsAg) has previously been shown to occur in mice and humans through transplantation of bone marrow cells from donors immunized against HBsAg (anti-HBs) to non-immune recipients. In the present study we evaluated the effect of adoptive transfer of immunity to HBsAg on the growth of HbsAg-secreting hepatocellular carcinoma (HCC) xenografts in athymic mice. METHODS: Immunocompetent mice were immunized with recombinant HBsAg. Bone marrow cells from anti-HBs+ mice were injected intravenously to irradiated athymic Balb/c mice which had been previously transplanted subcutaneously with Hep3B human hepatoma cells. Treatment groups included mice receiving bone marrow transplantation from HBV-immunized (anti-HBs positive) and non-immunized (anti-HBs negative) donors. RESULTS: At 9 weeks post bone marrow transplantation, tumor volume and serum alpha-fetoprotein levels in athymic mice receiving HBV-immune bone marrow cells were 11.5 mm3 and 363 ng/ml, respectively, as compared to 1579 mm3 and 19,000 ng/ml, in recipients of non-immune bone marrow transplantation (p<0.005). T-cell depletion of antiHBs+ immune bone marrow prior to transplantation decreased the anti-tumor effect but did not abolish it. A mild nonspecific, bone marrow-derived, graft versus tumor effect was observed in mice transplanted with human hepatoma cells that do not express HBsAg. CONCLUSIONS: Adoptive transfer of immunity to HBV facilitates suppression of experimental human HCC expressing HBsAg. This effect is the result of a combination of specific anti-viral surface antigen effect and a nonspecific graft versus tumor effect.

Adoptive Transfer↗
PubMed1981

Enrichment and expansion of specific antibody-forming cells by adoptive transfer and clustering, and their use in hybridoma production.

Adoptive transfer regimens have been examined as a method of enriching and expanding antibody-forming cells (AFC). When spleens from mice which had reverted to memory or from those at the peak of an AFC response were transferred to syngeneic irradiated recipients, a comparable enrichment in AFC of about 10-fold was found. However, recently re-stimulated spleen cells gave much better expansion of total AFC in the recipient mice. The degree of expansion was examined using different routes and timing of antigen stimulus and AFC recovery. With the optimum protocol found the AFC pool obtained from adoptively-transferred recipients was on average 80-fold greater than from conventionally re-immunised mice in a number of experiments. Further enrichment of the AFC was shown by an in vitro clustering technique which gave suspensions with AFC enriched to better than 1 cell in 10. Cluster-enriched and adoptive-transfer enriched populations were both shown to give a much higher incidence of successful specific hybridoma production than spleen cells from conventionally re-immunised mice.

Animals↗
PubMed1993

Complete Freund's adjuvant-induced T cells prevent the development and adoptive transfer of diabetes in nonobese diabetic mice.

Insulin-dependent diabetes mellitus is an autoimmune disease that is characterized by the destruction of insulin-producing beta cells in the islet of Langerhans. We have recently reported that the induction of the disease in nonobese diabetic (NOD) mice can be prevented by a single injection of CFA. In this study, we have explored the cellular basis and the time course of the disease protection. Since CFA contains a mycobacterial cell wall that has adjuvant property, we investigated the protective role of mycobacteria in young NOD mice. Mice injected with Mycobacterium tuberculosis or Mycobacterium bovis (BCG vaccine) at 4 wk of age were also found to be protected from diabetes. We have found that complete protection from diabetes is only achieved by administration of CFA between 4 and 10 wk of age. Draining lymph node cells or spleen cells from CFA-treated NOD mice transfer the protection. Adoptive transfer of spleen cells from CFA-treated mice with spleen cells from acutely diabetic mice delayed the induction of disease into irradiated recipient mice. CFA-treated old NOD mice were also resistant to passive transfer of disease by spleen cells from acutely diabetic mice. Depletion of the Thy 1.2+ cells or CD4(+)-bearing T cells abrogated the protection. However, disease can be induced in the protected mice by cyclophosphamide treatment. We also found that thymocytes from NOD mice responded only weakly to mitogen Con A. CFA treatment, however, restored the ability of these cells to respond to Con A. Finally, our results suggest that T cells induced after CFA treatment of NOD mice prevent both the induction and effector phases of the disease.

Animals↗
PubMed1982

Adoptive transfers of transplantation tolerance in genetically different strain combinations of mice.

Neonatal transplantation tolerance was induced in strain combinations of mice involving differences in the H-2D or H-2K regions, in the K or D ends of H-2, or in the central I region of the H-2 complex. Attempts were made to transfer the tolerance adoptively by suppressor cells to syngeneic non-immunosuppressed recipients. Adoptive transfer of tolerance was successful only in the combination with H-2D region disparity, and significant but short-lasting prolongation of skin allograft survival time was also obtained in the combination disparate at the D end of H-2. Transfers of tolerance were not successful in the combinations involving differences in the K or I regions of the H-2 complex irrespective of whether cells were transferred one day before or four days after skin grafting. The results are discussed with respect to hitherto known antigenic and tolerogenic properties of individual H-2 regions.

Animals↗
PubMedDate not supplied

Survival, persistence, and progressive differentiation of adoptively transferred tumor-reactive T cells associated with tumor regression.

Objective clinical responses have been observed in approximately 50% of patients who received non-myeloablative chemotherapy prior to the adoptive transfer of autologous melanoma-reactive tumor-infiltrating lymphocytes (TILs). Recent studies carried out through the use of antibodies directed against T-cell-receptor beta chain variable region (TRBV) products, as well as by direct sequencing of the expressed TRBV gene products, indicated that clinical responses in this trial were associated with the level of persistence of adoptively transferred T cells. In an attempt to further characterize T cells that persist in vivo following adoptive transfer, five dominant T-cell clonotypes were identified in TIL 2035, an adoptively transferred TIL that was associated with the complete regression of multiple metastases. The most highly persistent clonotype, which expressed the BV1 TR gene product, recognized the MAGE-6 cancer/testis antigen in the context of HLA-A23. This clonotype was detected in peripheral blood for over 16 months following adoptive transfer, expressed relatively higher levels of the co-stimulatory markers CD28 and CD27, and possessed telomeres that were long relative to other clonotypes present in TIL 2035 that showed only short-term persistence. The long-term persistent BV1 clonotype appeared to differentiate more slowly toward an end-stage effector in vivo than short-term persistent clonotypes, as manifested by the downregulation of CD28, CD27, and CD45RO and upregulation of CD57 and CD45RA expression on these T cells. These results indicated that the differentiation stage and replicative history of individual TIL clonotypes might be associated with their ability to survive and to persist in vivo, and progressive differentiation of the persistent clonotypes occurred following adoptive transfer.

Adult↗