High-dose chemotherapy and adoptive immunotherapy in the treatment of recurrent pediatric brain tumors.

Pediatric patients with recurrent brain tumors have a poor prognosis and limited therapeutic options. We investigated the use of high-dose chemotherapy with adoptive immunotherapy for recurrent brain tumors. Three pediatric patients with recurrent brain tumors received high-dose chemotherapy. This was followed by adoptive transfer of ex-vivo expanded T-cells. The T-cells were generated from peripheral blood after immunization with autologous cancer cells. The objectives of this study included (1) establishing the safety and feasibility of this potential treatment, (2) measuring changes in immune response after high-dose chemotherapy and adoptive immunotherapy, and (3) determining whether adoptive immunotherapy would be able to translate into a clinical response. Immune function was tested in all patients at the time of enrollment into the study. Humoral responses to recall antigens delayed-type hypersensitivity (DTH) were intact in all patients. After immunizing patients with autologous cancer cells, peripheral blood lymphocytes were harvested and activated with anti-CD3, expanded in-vitro, and infused post-autologous transplant. Patients received at least three doses of the vaccine, each consisting of an intradermal administration near a draining lymph node at biweekly intervals. Toxicity was limited and well tolerated in all patients. All three patients showed a tumor-specific immune response by serial imaging. Responses were durable at 16, 23, and 48 months, respectively.

A pilot study of autologous cancer cell vaccination and cellular immunotherapy using anti-CD3 stimulated lymphocytes in patients with recurrent grade III/IV astrocytoma.

The study objectives were to determine; (1) whether activated T cells could be generated from peripheral blood of patients immunized with their own cancer cells, (2) whether adoptive transfer of the activated T cells to patients had toxic effects and (3) whether the infused cells produced clinical responses. Study patients had recurrent, surgically accessible grade III/IV astrocytomas. The patients were tapered off steroids after total surgical resection and immunized with autologous cancer cells plus Bacillus, Calmette and Guerin (BCG). Peripheral blood mononuclear cells were activated with anti-CD3, expanded with interleukin-2 (IL-2) and reinfused to patients. The number of activated T cells that was given back to patients varied between 10(10) and 10(11). Side effects that were observed following immunization and adoptive cell transfer included mainly transient flu-like symptoms. One patient's tumor partially regressed, but there was no effect on survival. Two other patients' tumors regressed, and the patients are apparently disease-free more than 5 and 4 years later. The other six patients' tumors were apparently unaffected by the treatment. Patient age, tumor grade and CD4/CD8 composition of infused cells were positively correlated with clinical responses. Cellular immunotherapy is feasible and is associated with minimal toxicity. Additional appropriately controlled studies will be required to determine whether cellular immunotherapy could be used as a treatment for central nervous system malignancy. Additional studies also will be required to determine the underlying immunological mechanisms.

Nonoperative treatment of ipsilateral fractures of the scapula and clavicle.

BACKGROUND: Internal fixation of one or both bones is the recommended treatment for floating shoulder injuries (ipsilateral fractures of the scapula and clavicle). Perceived risks of nonoperative treatment include abduction weakness, decreased range of motion, chronic pain, malunion, and nonunion. None of these problems, however, have been confirmed by clinical studies. The purpose of this retrospective study was to analyze the clinical and radiographic results of nonoperative treatment of floating shoulder injuries. METHODS: Twenty patients with a floating shoulder injury were treated with either a sling or a shoulder immobilizer. Eleven clavicular fractures were displaced ten millimeters or more, and five scapular fractures were displaced more than five millimeters. Physical therapy was begun three days to two weeks after the injury. Patients were evaluated with three separate scoring systems: those of Herscovici et al., Rowe, and Constant and Murley. Shoulder abduction and flexion were measured, and abduction strength was evaluated by clinical examination and comparison with the uninjured extremity. The duration of follow-up averaged twenty-eight months (range, nine to seventy-nine months). RESULTS: Nineteen of the twenty pairs of fractures united uneventfully. One clavicular nonunion occurred secondary to segmental bone loss from a gunshot wound. On the basis of the Herscovici rating system, seventeen patients had an excellent result and three had a good result. According to the Rowe system, eighteen patients had an excellent result, one had a good result, and one had a fair result. The average Rowe score was 95. The average Constant score was 96. In all twenty patients, the strength of the injured extremity was equal to that of the uninjured extremity. Eighteen patients had a full, symmetrical range of shoulder motion, one lost 15 degrees of flexion, and one lost 20 degrees of abduction. CONCLUSIONS: Nonoperative treatment of floating shoulder injuries, especially those with less than five millimeters of fracture displacement, can achieve satisfactory results that are probably equal or superior to those reported after operative treatment, without the risk of operative complications.

Expression and regulation of histidine decarboxylase mRNA expression in the uterus during pregnancy in the mouse.

It has been hypothesized that hormonally regulated histamine production plays a role in preparation of the uterus for implantation. Histidine decarboxylase (HDC) is the rate-limiting enzyme for histamine production. The current study was designed to determine intrauterine expression of HDC mRNA expression during pregnancy in the mouse. High levels of HDC mRNA expression were observed in the preimplantation mouse uterus with peak expression occurring on day 4. High levels of HDC mRNA expression were also detected in the post-implantation uterus. In an effort to determine whether HDC mRNA is regulated by pro-inflammatory cytokines, the HDC mRNA pattern was compared to intrauterine expression of mRNA's for interleukin-1alpha (IL-1alpha), IL-1beta, macrophage chemotactic protein-1 (MCP-1) and RANTES (regulated on activation, normal T expressed and secreted) during the peri-implantation period. IL-1beta, MCP-1 and RANTES mRNA levels were increased in the uterus on days 1-2 and on days 4-5. Increased expression of IL-1alpha mRNA was observed on days 1-2 and days 5-7. There was no clear relationship between HDC mRNA expression and cytokine/chemokine mRNA expression. Progesterone-stimulated intrauterine expression of HDC mRNA. Intrauterine cytokine/chemokine mRNA was also hormonally regulated. This data allowed the possibility that one or more of these pro-inflammatory cytokines could be involved in regulating intrauterine HDC mRNA production. Recombinant IL-1alpha, IL-1beta, MCP-1 and RANTES all failed to induce HDC mRNA expression in the preimplantation uterus in a mouse pseudopregnancy model. At the same time, IL-1beta induced the expression of mRNA for each of the four cytokines/chemokines. Despite the fact that these were also produced in the uterus during pregnancy and were hormonally regulated, none of these cytokines induced intrauterine HDC mRNA expression. The data suggest that progesterone is involved in the regulation of HDC mRNA expression in the preimplantation uterus, but IL-1alpha/beta, MCP-1 and RANTES, which have been reported to regulate histamine synthesis during inflammatory processes, do not appear to play a role.

Immune rejection of intracerebral gliomas using lymphocytes from glioma-bearing rats.

Naturally occurring malignancies do not induce immune responses against cancer antigens. Is the lack of an immune response caused by an antigen presentation defect or by induced antigen-specific immune suppression? The current study was performed to determine whether a progressing intracerebral malignancy affects production of peripheral autologous glioma antigen-specific immune responses. Peripheral immunization of both glioma-bearing and non-glioma-bearing animals with cancer cells and adjuvant generated similar levels of glioma antigen-specific cytotoxic T lymphocyte activity. However, immune cell populations from glioma bearers were significantly less efficient than immune cell populations from non-cancer bearers in their ability to reject progressing intracerebral tumors. A variety of manipulations designed to reduce nonspecific immune suppression in vivo and in vitro had no effect on the in vivo efficacy of the activated T-lymphocyte populations. The presence of progressing tumors appeared to augment rather than suppress cancer antigen-specific responses, leading to the speculation that reduced efficacy was caused not by generalized immune suppression but rather by a reduction in the number of immune effector cells by either clonal anergy or clonal deletion. Most importantly, the data demonstrated that, despite decreased in vivo efficacy, immune effector cells capable of rejecting an intracerebral malignancy could be generated from cancerous hosts.

Expression and regulation of chemokine genes in the mouse uterus during pregnancy.

Leukocytes accumulate in the pregnant mouse uterus following mating, during implantation and during placental development. Changes in leukocyte number are primarily due to recruitment from the blood, not local proliferation, but the underlying recruitment mechanisms are poorly understood. Mating-induced granulocyte and macrophage recruitment is due in part to pro-inflammatory and chemotactic factors present in seminal plasma. Accumulation of macrophages later in pregnancy appears to be caused in part by ovarian hormone-stimulated CSF-1 production and in part by other as yet unidentified uterine chemotactic factors. The current study was performed to assess chemokine production in the uterus during pregnancy. Northern blotting was used to demonstrate NSI/KC (KC), macrophage chemotactic protein-1 (MCP-1), macrophage inflammatory protein one alpha (MIP1alpha) and regulated inactivation, normal T expressed and secreted protein (RANTES) mRNA in the uterus. Oestrogen and progesterone induced intrauterine production of all four chemokines and may have done so through the autocrine/paracrine activities of IL-1. The data suggest that C-C chemokines play a role in accumulation of macrophages in the uterus during pregnancy.

Low-velocity gunshot injuries of the spine with abdominal viscus trauma.

OBJECTIVE: To evaluate the risk of infection of the spine and associated complications after colonic or rectal injury associated with gunshot injury of the spine. DESIGN: Retrospective review. SETTING: Presley Memorial Trauma Center, Regional Medical Center, Memphis, Tennessee, a statewide Level 1 trauma center. PATIENTS: Thirty-three patients with gunshot wounds to the spine and associated viscus injury were treated between 1989 and 1994; in thirteen, the bullet passed through the colon or rectum before damaging the spine. INTERVENTION: Six patients received a single antibiotic (Cefotetan) and seven were given multiple antibiotics. Total duration of antibiotic treatment ranged from two to forty-three days. RESULTS: None of the thirteen patients developed osteomyelitis or disc space infection. Most intraabdominal complications were secondary to dehiscence of colonic repair. CONCLUSIONS: Because the magnitude of bacterial colonization of the vertebrae after colonic injury may not be high, a nonoperative approach to treatment of abdominal viscus injuries is appropriate in patients with gunshot wounds to the spine. Broad-spectrum antibiotic coverage for at least seven days appears to be effective in preventing spinal infection, but colonic injuries are associated with an increased incidence of intraabdominal abscess and peritonitis.

Selective chemokine mRNA expression following brain injury.

Injury in non-neuronal tissues stimulates chemokine expression leading to recruitment of inflammatory cells responsible for orchestration of repair processes. The signals involved in directing repair of damage to the brain are less well understood. We hypothesized that following brain injury, chemokines are expressed and regulate the rate and pattern of inflammatory cell accumulation. The two chemokine subfamilies are alpha(alpha)-chemokines, which primarily function as neutrophil chemoattractants, and the beta(beta)-chemokines, which function primarily as monocyte chemoattractants. We assessed alpha and beta chemokine mRNA expression patterns and leukocyte accumulation following a cerebral cortical lesion. Cortical lesions were produced with and without addition of endotoxin, Escherichia coli lipopolysaccharide (LPS), which stimulates cytokine expression. We studied the expression of the beta-chemokines: monocyte chemoattractant protein (gene product JE; MCP-1/JE), macrophage inflammatory protein-1 alpha and beta (MIP-1alpha and MIP-1beta), and the regulated upon activation normal T expressed and secreted chemokine (RANTES) as well as the alpha-chemokines: interferon-gamma-inducible protein (IP-10) and N51/KC (KC; a murine homologue of MIP-2). Changes in gene expression were analyzed by Northern analysis at different time points following injury. Leukocyte and macrophage densities were analyzed by immunohistochemistry at the same time intervals. All chemokines were elevated following cortical injury/endotoxin. MCP-1 and MIP-1alpha were elevated at 2 h and peaked 6 h, MIP-1beta peaked at 6 h, but declined more rapidly than MCP-1 or MIP-1alpha, and IP-10 peaked at 6 h and showed the most rapid decline. KC was elevated at 1 h, and peaked at 6 h following LPS. RANTES was elevated at 1 h and achieved a plateau level between 6 and 18 h, then declined. In contrast, sterile injuries produced in the absence of endotoxin only induced the mRNA of the beta-chemokine MCP-1, and its expression was delayed compared to the cortical injury/endotoxin group. The presence of chemokine message as early as 1 h indicates that expression of this class of molecules is an early response in the repair process following traumatic brain injury. Macrophage/microglia accumulation occurred more rapidly, activated microglia further from the lesion border, and more cells accumulated in cortical injury/endotoxin than in cortical lesions produced under sterile conditions. Thus, there was a positive correlation between beta-chemokine expression and the number of beta-chemokine responsive cells (i.e. microglia) accumulating in injury sites. This is the first comprehensive study using a panel of chemokine probes and specific marcophage/microglial markers to study in vivo activation of the brain following injury. Our data show that the brain is capable of expression of multiple chemokine genes upon appropriate stimulation (e.g. LPS-treatment). The gradient of microglial activation is consistent with physical damage stimulating release of chemokines that diffuse from the injury site. These data strongly suggest that chemokines are instrumental in the initiation of repair processes following brain injury.

Endotoxin-induced abortion in mice is mediated by activated fetal macrophages.

Leukocyte numbers and function were assessed in uterus, placenta, and fetus during endotoxin-induced abortion. Tissues initially contained high numbers of macrophages but no granulocytes or lymphocytes. Endotoxin treatment resulted in rapid, transient neutrophil accumulation in uterus and placenta. Moderate increases in macrophage numbers occurred in the uterus but there were no changes in tissue distribution. Myometrial, endothelial, and epithelial cells were unaffected by endotoxin but proliferating, differentiated fibroblasts that made up the primary decidua disappeared. As abortion progressed, the proportional representation of macrophages in placenta and embryo increased until, during the late stages of fetal resorption, they constituted nearly all viable fetal cells. At the same time, overall expression of class II major histocompatibility complex gene products increased in maternal and fetal tissue. Leukocyte distribution and macrophage activation data suggested that endotoxin-induced fetal failure is mediated by products of activated maternal and fetal macrophages acting in concert to destroy actively proliferating maternal and fetal cells.

The nucleotide sequence of the HA1 of the haemagglutinin of an HI avian influenza virus isolate from turkeys in Germany provides additional evidence suggesting recent transmission from pigs.

The nucleotide sequence encoding the HA1 portion of the haemagglutinin gene of the influenza virus A/turkey/Germany/2482/90j isolated from birds kept in an area of many pig farms, was determined and compared with those of recent avian and swine influenza isolates. It was found to be closest to the 'avian-like' swine H1N1 influenza viruses that have been reported in Europe since the early 1980s and may represent good evidence for transmission of these viruses back to birds after they have become established in pigs.

Relative role of CSF-1, MCP-1/JE, and RANTES in macrophage recruitment during successful pregnancy.

It has been previously demonstrated that macrophage colony stimulating factor (CSF-1) is produced by uterine epithelial cells in response to estrogen and progesterone. Studies in normal and op/op mice demonstrated that accumulation of a portion of the uterine macrophage population could be attributed to the chemotactic properties of CSF-1. Op/op mice exhibit greatly reduced rates of fertility, but successful pregnancy is not completely blocked. Also, uteri from op/op mice are not completely macrophage deficient. There are two possible explanations for this. One is that not all tissue macrophages are recruited from the bone marrow pool; some may be derived from primitive mesenchyme. Alternatively, tissue macrophages may be recruited from the bone marrow pool through expression of other type 1 chemokines such as JE, RANTES, MIP-1 alpha, MIP-1 beta, IP-10, and KC. Both RANTES and JE are expressed at higher levels than CSF-1 during early pregnancy. The variable expression and relative role of these various chemokines in pregnancy was addressed by measuring mRNA expression during the first 8 days of pregnancy and in a pseudopregnant model. The expression of these various genes relative to macrophage numbers and macrophage distribution will be discussed. The relative role of these various factors in preparing the uterus for blastocyst implantation will be discussed.

An avian influenza virus of H10 subtype that is highly pathogenic for chickens, but lacks multiple basic amino acids at the haemagglutinin cleavage site.

Avian influenza virus isolate A/mandarin duck/Singapore/805/F-72/7/93 was found to be consistently highly pathogenic by recognised in vivo testing procedures although it was of a subtype (H10) not usually associated with high pathogenicity. The virus was also not typical of highly pathogenic influenza viruses in that it was not pathogenic when administered intra-nasally, did not possess a haemagglutinin cleavage site with multiple basic amino acids and did not replicate in the brains of chickens after intravenous inoculation. A re-examination of the earlier H10 isolate A/turkey/England/384/79 suggested that it was similarly pathogenic. The pathogenicity may have been associated with replication in the kidney.

The efficacy of pedicle screw/plate fixation on lumbar/lumbosacral autogenous bone graft fusion in adult patients with degenerative spondylolisthesis.

A total of 18 patients with grade I or II degenerative spondylolisthesis fused three levels or fewer with autogenous bone graft were entered at three clinical sites. After 2 years, these patients were found to have a fusion rate of 89%. A statistical analysis of these results compared with those in the literature showed that patients with spondylolisthesis who underwent fusion with pedicle screw instrumentation were > 3 times more likely to fuse than comparable patients implanted without a pedicle screw/plate system. The pedicle screw/plate system used in this study was shown to be an effective method of facilitating lumbar or lumbosacral fusion with autogenous bone graft for adult patients with a primary indication of grade I or II degenerative spondylolisthesis.

Autologous tumor cell vaccination combined with adoptive cellular immunotherapy in patients with grade III/IV astrocytoma.

Brain tumors are highly resistant to treatment. Their diffuse infiltrative nature and the relative inaccessibility of the brain to blood and lymph are barriers to surgical and cytotoxic treatments alike. Preclinical animal studies demonstrated that intravenously administered tumor antigen-specific T lymphocytes will reject tumors growing in the brain. Specifically activated effector T lymphocytes may be generated by in vivo immunization followed by restimulation of antigen-primed T cells with autologous tumor cells in vitro. In order to apply these findings to humans, feasibility studies of combined active immunization and specific adoptive cellular immunotherapy were performed on fifteen patients with recurrent astrocytoma. The objective was to determine whether; 1) T cells could be grown from peripheral blood of patients immunized with autologous tumor cells, and 2) whether stimulated cells could be safely readministered to patients. Patients were immunized with a combination of their own irradiated tumor cells and Bacillus of Calmette and Guerin. Two weeks later a mononuclear cell-rich fraction of blood was obtained by leukapheresis. Mononuclear cells were cultured with irradiated autologous tumor cells and interleukin-2. Selective expansion of CD4+ and CD8+ T lymphocytes occurred. Intravenous transfer of stimulated cells to the fifteen patients on twenty-four separate occasions with or without systemic administration of interleukin-2 was tolerated with limited toxicity. The studies established the feasibility of conducting controlled studies of the anti-tumor effects of tumor antigen-specific cellular immunotherapy.

Replication of influenza A viruses of high and low pathogenicity for chickens at different sites in chickens and ducks following intranasal inoculation.

Ten specific pathogen free light breed chickens and 10 commercial layer ducks were inoculated intranasally with one of five avian influenza A viruses which had been characterised as showing high or low pathogenicity for chickens. Recovery of the two viruses of low pathogenicity was restricted to the respiratory tract and gut of both species. Highly pathogenic viruses were recovered from all organs sampled. With two of the highly pathogenic viruses, A/duck/Ireland/113/83 (H5N8) and A/chicken/Victoria/85 (H7N7), the sites of recovery in ducks were similar to those seen in chickens except that virus was absent from the brain, apart from low levels detected in brain samples taken on day 5 from ducks infected with A/duck/Ireland/113/83. The levels recovered from organs of ducks for these two viruses were also similar to those in chickens, except for lower levels in kidney and liver for ducks infected with A/chicken/Victoria/85, and a delayed peak of recovery of both viruses in ducks. The third.highly pathogenic virus, A/turkey/England/50-92/91 (H5N1), could not be recovered from any site in ducks. For all three highly pathogenic viruses mortality and morbidity were rapid and complete in chickens but absent in ducks.

The effect of pedicle screw/plate fixation on lumbar/lumbosacral autogenous bone graft fusions in patients with degenerative disc disease.

STUDY DESIGN: A prospective, multi-center Investigational Device Exemption Study was carried out in the United States using a pedicle screw and plate system to perform a fusion in patients with degenerative disc disease or spondylolisthesis. The patients' pain function, complications, and fusion status were evaluated and compared with literature controls. OBJECTIVES: To study the safety and efficacy of the ISF pedicle screw/plate system. This article focuses only on those study patients with degenerative disc disease treated with autogenous bone grafts and compares the results to those of similar patients treated without instrumentation, as reported in the literature. SUMMARY OF BACKGROUND DATA: Twenty-eight patients were in the subgroup studied--patients with degenerative disc disease who had fusions with autogenous bone graft. This study was conducted at four clinical sites with a 2-year follow-up. Patient follow-up was greater than 95% at all time points. METHODS: To be considered a patient with degenerative disc disease, radiographs had to demonstrate a collapse of the disc, the presence of bone erosion, or the compression of the vertebrae as the primary spinal abnormality. Spinal fusion must have been the recommended surgical treatment for discogenic pain. The fusion status was evaluated by the operating surgeon and an independent reviewer. RESULTS: After 2 years, this subset of patients (n = 28) with degenerative disc disease who had lumbar/lumbosacral fusion with autogenous bone graft was found to have a pseudarthrosis rate of 0%. Eight articles in the literature were found to be valid noninstrumented literature controls with which this subgroup could be compared. The average pseudarthrosis rate in the control group was 32%. CONCLUSIONS: A statistical analysis showed that patients with degenerative disc disease who underwent fusion without pedicle screw instrumentation were over 24 times more likely to have a pseudarthrosis than comparable patients implanted with a pedicle screw/plate system. Regarding the most important goal in performing a spinal fusion--fusion of the spine--the pedicle screw/plate system used in this study was shown to be a safe and efficacious method of facilitating fusion with autogenous bone graft for this patient population.

Is restricted antigen presentation the explanation for fetal allograft survival?

Mammalian embryos express paternal histocompatibility antigens which make them potential targets for the maternal immune system. The trophoblast is a major histocompatibility complex (MHC) antigen-negative barrier between mother and fetus which facilitates movement of antigenic molecules but prevents traffic of antigenic cells and is itself unable to present antigen. Gary Wood suggests that the lack of antigen presentation requirements for MHC class I-restricted T-cell responses prevent generation of paternal-antigen directed cell-mediated immunity.

Deduced amino acid sequences of the haemagglutinin of H5N1 avian influenza virus isolates from an outbreak in turkeys in Norfolk, England.

The deduced amino acid sequences of the haemagglutinins of avian influenza viruses, isolated from an outbreak in turkeys in Norfolk, England in 1991/92, were determined by PCR amplification and cycle sequencing. Both the highly pathogenic and avirulent isolates had the same cleavage site sequence with multiple-basic amino acids, which normally would be expected only for the former. Clones derived by plaque picking from the highly pathogenic isolate ranged from low to very high pathogenicity in vivo and these, and the original isolates, showed nucleotide and amino acid variation at one or more of five possible sites, none of which were at the cleavage site. None of these site variations correlated with pathogenicity, suggesting that the factor responsible for the suppression of the expected effects of the multiple-basic amino acid haemagglutinin cleavage site in the avirulent isolate may not have been part of the haemagglutinin amino acid sequence.

Generation of cytotoxic immune responses during the progression of a rat glioma.

Cytotoxic T lymphocytes specific for tumor-associated antigens are produced by exposing animals to tumor cells and stimulating lymphocytes from animals immunized in vitro with tumor cells and small amounts of interleukin-2 (IL-2). This study was designed to determine whether a fast-growing immunogenic avian sarcoma virus-induced glioma produces primed cytotoxic T lymphocyte precursors during its progression. Lymphocytes from intracerebral glioma-bearing rats generally failed to proliferate in vitro in response to immunization with tumor cells and IL-2 and, when proliferative responses were observed, the lymphocytes were not cytotoxic for glioma cells. However, when the same tumor was growing subcutaneously, lymphocytes proliferated and exhibited glioma-specific cytotoxicity when stimulated in vitro with autologous tumor cells and IL-2. Subcutaneous immunization of intracerebral glioma-bearing rats with tumor cells and adjuvant induced strong cytotoxic T lymphocyte responses. The results demonstrated that, while intracerebral tumor progression itself does not induce an anti-glioma immune response, immune responses to tumor-associated antigens may be induced by systemic immunization of tumor-bearing animals. The results suggest that the immunogenicity of brain tumors is masked by the immunologically privileged status of the brain, not by the induction of generalized immune suppression during tumor progression.

Immune system of the spontaneously hypertensive rat: II. Morphology and function.

The spontaneously hypertensive rat (SHR) is a stress-sensitive animal which exhibits moderate immune dysfunction that has been implicated in the onset of hypertension. In this study, we examined the morphology of SHR thymus and spleen and further characterized the immune deficiency using Wistar-Kyoto (WKY) and Fisher 344 (F-344) rats for comparison. The adult SHR thymus does not display the increase in medullary volume typically noted with aging and the volume density of the marginal zone is decreased in the spleen. In vivo tritiated-thymidine incorporation is also decreased in the spleen of unstimulated SHR. In mixed lymphocyte reactions (MLR), the proliferative response of SHR splenocytes is significantly decreased relative to controls, WKY and F-344. Addition of interleukin-1 (IL-1), interleukin-2 (IL-2), or indomethacin to the MLR cultures does not increase proliferation. The proliferative response to T cell receptor monoclonal antibody (mAb-TCR) or interleukin-2 (IL-2) are similarly impaired in the SHR. The depressed proliferative T cell response is reversed by prolactin. It is suggested that the SHR is a valuable model for the study of immune deficiency.