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PubMed1999

Advantages of a new miniature hearing aid for mild to moderate hearing loss.

OBJECTIVES/HYPOTHESIS: To evaluate the performance of a new, miniature, behind-the-ear hearing aid designed for individuals with mild to moderate high-frequency hearing loss who need an aid but are reluctant to try one. The aid is essentially invisible, leaves the ear canal open, and can be fit in less than 30 minutes without an ear impression. The cost is less than $500. STUDY DESIGN: A 4-week trial of the aid in 63 ears (62 subjects) with mild to moderate bilateral hearing loss. METHODS: A questionnaire was completed at the end of the study by each subject asking them to evaluate several features of the aid (cosmesis, comfort, understanding speech, amplification, and so forth) and to compare their unaided performance in quiet and in noise with the test hearing aid. A rating scale of 1 to 10 was used, with 10 being excellent and 1 poor. RESULTS: Subjective improvement in understanding speech in both quiet (5.8-->7.3) and noise (4.6-->5.9) occurred with the aid. Cosmesis, comfort, and appearance were highly rated (mean scores, > 8). CONCLUSIONS: This aid appears to have several features (comfort, cost, performance, and cosmesis) that make it ideal as a first aid for patients with mild to moderate losses.

Adult↗
PubMed1991

Reproducibility of renal blood flow estimation in the miniature pig using 99Tcm-DTPA: introducing semiautomatic processing.

This study examines the reproducibility of renal blood flow measurement (RBF) in nine miniature pigs using 99Tcm-DTPA renography, and introduces a new algorithm useful in data processing. Renal blood flow can be estimated using three arterial regions of interest (ROI), the left ventricle (LV), the right lung (RL) and the aorta. Using the LV ROI, left kidney RBF was 9.08 (S.D. 1.69) and right RBF was 10.87 (S.D. 2.26). Reproducibility was assessed by performing renograms on successive days in nine pigs and was found to be best for LV [S.D. of change 0.32 for the left kidney (LK) and 0.74 for the right kidney (RK)] followed by RL (0.77 for LK and 0.75 for RK) and worst for aorta (1.47 for LK and 1.78 for RK).

Algorithms↗
PubMed1991

Estimation of glomerular filtration rate in the miniature pig by kidney uptake on the gamma camera.

Measurement of glomerular filtration rate (GFR) by the renal uptake of 99Tcm-diethylene triamine penta-acetic acid (99Tcm-DTPA) in the miniature pig was compared to that by plasma disappearance of 99Tcm-DTPA using multiple blood samples. Nineteen animals were examined under identical conditions. There was a highly significant relationship between the two tests, r = 0.88, P less than 0.001, although the uptake method gave consistently higher results than those obtained from plasma disappearance. Reproducibility of the uptake method was also assessed in this group of animals by performing two consecutive renograms. Confidence limits of 95% were +/- 7.5% or 0.7 ml min-1 kg-1. The test is useful for the serial examination of single kidney GFR on follow-up renography but is unlikely to replace disappearance techniques as a more accurate means of GFR estimation.

Animals↗
PubMed1990

Long-term effects of tissue expansion on cranial and skeletal bone development in neonatal miniature swine: clinical findings and histomorphometric correlates.

Progressive tissue expansion induces significant gross, histologic, and bony changes in skulls and long bones of neonatal miniature swine. These bony changes consist of erosion underlying tissue expanders, with bony lipping and bone deposition at the periphery of the expander. Cranial suture lines underneath expanders appear effaced and convoluted. Serial CT scans reveal decreased bone thickness and volume (p less than 0.02) but identical bone density (p = 0.60) beneath expanders. Increased bone volume and thickness occur at the periphery of expanders (p less than 0.02). Bone density (CT number) is unaffected by tissue expansion in both cranial and long bones. These findings have histomorphometric correlates: Osteoclastic bone resorption occurs underneath expanders with periosteal reaction at the periphery of expanders. Cranial sutures are similarly affected, but no cranial synostosis results. No changes to the inner table of the skull or stigmata of increased intracranial pressure were observed either in CT scans or in behavioral changes in long-term animals. The pathophysiology of bony changes is a remodeling effect, not one of simple pressure deformation. Increased bone resorption and complete inhibition of bone formation occur until the pressure is removed. Cranial bone is significantly more affected than long bone. After removal of the expanders, reparative bone remodeling begins within 5 days and nearly complete healing of the cranial defects occurs within 2 months (p less than 0.02). No plagiocephaly results despite early coronal suture changes. On the basis of this study, we conclude that tissue expansion causes significant but reversible effects, readily monitored by high-resolution CT scans, on neonatal and infant cranial and long bones.

Animals↗
PubMed1993

Experimental rectus abdominis myocutaneous and rectus abdominis myoperitoneal flaps as urinary bladder wall substitutes in miniature swine.

An experiment was performed in Yucatan miniature swine to determine the feasibility and characteristics of musculocutaneous or musculoperitoneal flaps as urinary bladder wall substitutes. In five swine, a single-pedicle skin island flap (rectus abdominis myocutaneous, RAM/C) was sutured into the bladder. In five other swine the flap was a peritoneum island (rectus abdominis myoperitoneal, RAM/P). Three swine were sham-operated controls. The patches were in place for 20 weeks, remaining viable and elastic. Inflammation, maceration, and infection were absent. Skin patch histology was unchanged. The peritoneal patches became resurfaced with uroepithelium. The sham bladder volume (ml/kg body weight) did not differ significantly from RAM/P bladder volume (p = 0.54). RAM/C bladders were slightly smaller than shams (p = 0.11) and significantly smaller than RAM/P bladders (p = 0.03). Substitution of the bladder wall with RAM patch flaps is feasible. This is an important preliminary step toward our goal of nonenteral urinary bladder wall substitution.

Abdominal Muscles↗
PubMed1984

Fetal pancreas transplantation in miniature swine. I. Developmental characteristics of fetal pig pancreases.

The genetically defined miniature pig developed by Sachs et al. was selected as a large animal model to test the feasibility of fetal pancreas transplants for reversal of insulin-dependent diabetes. In order to test our approach, the first key was to characterize the development of the pig pancreas tissues throughout fetal life. Pancreas samples were obtained from 102 farm pig fetuses ranging in age from 35-110 days and from 39 minipig fetuses removed by Caesarean section from 5 timed-pregnant sows between 33 and 73 days after conception. The development of the endocrine and exocrine pancreases were examined by immunobiochemical assays of insulin, chymotrypsinogen, and trypsinogen. Light and electron microscopic examination of pancreases from the critical fetal ages (35-55 days) were used to confirm the above results. Insulin was already present at day 33 and increased rapidly till birth (day 114: 2.2 U/pancreas). Chymotrypsinogen activity was first detected at day 43 and trypsinogen activity at days 49-50. Enzyme content increased rapidly till days 65-70 and then more gradually until birth. Morphological development of exocrine cell granules conformed to the above results. The results clearly demonstrated in the pancreas of a larger mammal, the pig, that the endocrine elements mature prior to the exocrine system. Thus, as we found in rats, pig fetal pancreas also has this advantage as a donor tissue for transplantation. An appropriate fetal age for pig donors is estimated to be between 45 and 50 days.

Animals↗
PubMed1988

Bone marrow transplantation in miniature swine. I. Development of the model.

Procedures for successful autologous and MHC-matched allogeneic bone marrow transplantation in partially inbred, MHC-defined miniature swine have been established. All marrow recipients were conditioned with single-dose total-body irradiation at the upper level of tolerance, and supported with antibiotics and irradiated blood products during aplasia. Surgical harvest of autologous and allogeneic marrow yielded sufficient numbers of cells to successfully reconstitute recipients. Radiation control animals that received no marrow failed to show recovery of marrow function. Pigs transplanted with autologous marrow at doses greater than 10(8) cells/kg routinely engrafted and recovered normal marrow function. The major clinical complications were acute and chronic infections and hemorrhage. T cell-depleted autologous marrow also engrafted, and there was no observed increase in clinical complications. In bone marrow transplantation across non-MHC allogeneic differences, engraftment and survival were similar to that observed for autologous transplants. The T cell depletion of marrow in such MHC-matched allogeneic recipients was associated in one animal, however, with early reconstitution by cells of autologous origin.

Animals↗
PubMed1990

Mechanism of tolerance following class I--disparate renal allografts in miniature swine. Cellular responses of tolerant animals.

Previous studies utilizing a recombinant MHC haplo-type in our partially inbred miniature swine herd have demonstrated that some recipients matched only for SLA class II show long-term acceptance of renal allografts without exogenous immunosuppression. Such animals have been shown to develop systemic tolerance as evidenced by prolonged rejection times of subsequent donor-specific, but not third-party, skin grafts. In the present studies in vitro cellular responses of long-term tolerant animals and of 7 animals studied sequentially are presented. Long-term tolerant animals demonstrated responses consistent with the absence of the class I reactive helper populations normally present in naive controls. Animals studied sequentially segregated into two groups based on cellular reactivity and survival. All animals showed complete loss of antidonor class I cell-mediated lymphocytolytic (CML) reactivity by postoperative day 10. However, animals surviving less than 20 days maintained CML reactivity to donor class I plus third-party class II in the posttransplant period, while animals surviving greater than 40 days lost such reactivity. Addition of exogenous interleukin 2 could not reverse this loss. These studies suggest that tolerance induction to a renal allograft across a class I only difference involves effects on both helper and killer class I reactive cell populations.

Animals↗
PubMed1992

Successful induction of long-term specific tolerance to fully allogeneic renal allografts in miniature swine.

Major histocompatibility complex class II matching is of overwhelming importance for achieving tolerance to kidney transplants (KTX) in miniature swine. When class II antigens are matched, long-term specific tolerance across complete MHC class I antigen barriers can uniformly be induced by a 12-day perioperative course of cyclosporine. This same regimen is ineffective in fully MHC-mismatched combinations. We hypothesized that initial induction of tolerance to kidney donor class II antigens by bone marrow transplantation might allow tolerance to be induced to a subsequent fully allogeneic KTX in combination with CsA therapy. We report here the results of such fully allogeneic KTX performed in 4 recipients of prior single-haplotype class II-mismatched BMT. All animals received KTX from donors class II matched to the BMT donor and received a 12-day course of intravenous CsA (10 mg/kg/day). All four animals have maintained normal serum creatinine values (less than 2.0 mg/dl) for greater than 200 days posttransplant. Specific hyporesponsiveness to both BMT and KTX donor-type MHC antigens was found in mixed lymphocyte culture and cell-mediated lympholysis assays. Compared with third-party grafts, significantly prolonged survival of BMT donor-specific (P = 0.031) and KTX donor-specific (P = 0.031) skin grafts was observed. These results demonstrate that induction of tolerance to class II antigens by BMT allows a short course of CsA to induce specific tolerance to fully allogeneic renal allografts.

Animals↗
PubMed1992

Induction of specific tolerance to class I-disparate renal allografts in miniature swine with cyclosporine.

Previous studies in miniature swine have suggested that the mechanism underlying the spontaneous development of tolerance in one third of one-haplotype class I disparate renal allografts (i.e., ag----ad) involves a relative T cell help deficit at the time of first exposure to antigen. If this hypothesis were correct, then one might expect the administration of an immunosuppressive agent capable of inhibiting lymphokine production during this period to lead to the induction of tolerance to class I MHC antigens in two-haplotype class I mismatched renal allografts (i.e., gg----dd), which are otherwise uniformly and acutely rejected. This hypothesis was tested in eight two-haplotype class I disparate, class II matched donor-recipient pairs, in which recipients were treated with cyclosporine 10 mg/kg, i.v. q.d. for 12 days. This protocol led to the induction of long-term (greater than 100 days) specific tolerance in 100% of recipients, as compared with control animals that rejected grafts in 13.7 +/- 0.9 days (P less than 0.0001). The specificity of tolerance was assessed both in vivo with subsequent skin grafts and in vitro by mixed lymphocyte response (MLR) and cell-mediated lymphocytotoxicity (CML). Survival of donor-specific skin grafts was prolonged compared with skin grafts bearing third-party class I antigens (19.5 +/- 2.0 versus 11.5 +/- 2.0 days, n = 4, P less than 0.05). Tolerant recipients had markedly diminished or absent anti-donor MLR and CML responses, but maintained normal reactivity to third party. Four of eight CsA-treated recipients showed detectable levels of anti-donor IgM, while none demonstrated the presence of anti-donor IgG, which was found in all rejecting controls.

Animals↗
PubMed1994

Development of tolerance to class II-mismatched renal transplants after a short course of cyclosporine therapy in miniature swine.

Our laboratory has reported previously spontaneous acceptance of class II-matched, single haplotype (but not 2 haplotype), class I-mismatched renal allografts in miniature swine. All class II-mismatched animals rejected acutely regardless of class I matching. We have also demonstrated recently that a short course of high dose (10 mg/kg/day for 12 days) CsA uniformly induces donor-specific tolerance to 2-haplotype, class I-mismatched renal allografts. The survival of 2-haplotype, fully MHC mismatched renal allografts was prolonged by the same treatment, but tolerance was not induced, as all animals rejected eventually. We have now tested this short course of immunosuppressive therapy for its effect on renal allografts mismatched selectively for 2 haplotypes at class II. We have observed long-term graft survival in 5 of 7 animals under these conditions. Each of the 5 acceptor animals was demonstrated to be specifically tolerant by its response either to donor-matched skin grafts or to a second donor-matched kidney transplant without further immunosuppression. These data suggest the existence of a common pathway for induction of specific transplantation tolerance to MHC antigens when these antigens are recognized on vascular endothelium under conditions of altered cytokine production. They also suggest that tolerance induction under these conditions requires matching for either class I or class II antigens, which may have implications for the mechanism by which peripheral tolerance is induced, as well as practical implications for the extension of these results to potential clinical practice.

Animals↗
PubMed1995

Tolerance to class I-disparate renal allografts in miniature swine. Maintenance of tolerance despite induction of specific antidonor CTL responses.

Miniature swine that become tolerant to renal allografts across an MHC class I barrier following a short course of cyclosporine are unresponsive to donor class I antigens in cell-mediated lymphocytotoxicity. However, skin grafts bearing donor class I plus third-party class II antigens are promptly rejected, and the animals then develop marked cell-mediated lymphocytoxic reactivity to donor class I antigens in vitro, but do not reject the kidney transplants. We show here that CTL generation is directed toward the same donor class I antigens as are expressed by the kidney donor, and is not the result of recognition in vitro of the tolerated class I antigen plus peptides of minor antigens shared between the skin graft donor and the stimulator/target cells. We also show that detection by CTLs of peptides expressed by skin but not by kidney is also not a sufficient explantation of the results, since the survival of skin grafts from the kidney donor is also prolonged, even after precursor CTL can be detected in vitro. The data are most consistent with suppression in vivo in tolerant animals of the helper pathways necessary for activation of precursor CTLs. Differences in patterns of cytokine expression by graft infiltrating cells may provide a mechanism for local suppression of help in this model. Finally, we have examined antibody production after sensitizing by skin grafts in long-term tolerant animals and have found that anti-donor class I antibodies are not produced, even though the same animals produce both anti-class II and anti-third-party class I antibodies.

Animals↗
PubMed1997

Molecular and cellular events implicated in local tolerance to kidney allografts in miniature swine.

Long-term tolerance to class I-mismatched renal allografts can be induced in miniature swine by treatment with a short course of cyclosporine (CsA). Kidney recipients treated with CsA and untreated control kidney recipients both demonstrated infiltration of the transplanted kidney by mononuclear cells, which reached a maximum between postoperative days 8 and 11. Recipients that did not receive the tolerizing regimen rejected their grafts between postoperative days 8 and 12 in this model. The kinetics of cytokine gene expression, including interleukin (IL)-1alpha, IL-1beta, IL-2, IL-6, IL-10, tumor necrosis factor, and interferon-gamma (IFN-gamma), within the grafted kidney of rejector and acceptor animals, were determined using Northern blot hybridization. A strong correlation between rejection and up-regulation of the IFN-gamma gene was observed, whereas animals with long-term tolerance showed low levels of IFN-gamma, but high levels of IL-10 gene transcription. None of the other cytokine genes demonstrated a reproducible pattern of expression that correlated with acceptance/rejection of allografts. Analysis of transcription patterns of cytokine genes in mononuclear cells purified from renal grafts confirmed the initial observations made on biopsies. The phenotype of graft-infiltrating cells (GIC) showed a dominance of CD8+ cells, with an average of 66% single-positive cells and 19% CD4/CD8 double-positive cells, compared with 30% and 14%, respectively, for peripheral cells. Predominance of CD8+ GIC was dictated neither by the MHC antigen disparity nor the rejector/acceptor status. These results, therefore, suggest that GIC represent a regulated combination of mononuclear cells producing local immune mediators that, in part, control the fate of allografts in this large animal model.

Animals↗
PubMed1998

Mechanism of tolerance to class I-mismatched renal allografts in miniature swine: regulation of interleukin-2 receptor alpha-chain expression on CD8 peripheral blood lymphocytes of tolerant animals.

BACKGROUND: Donor-specific tolerance to renal allografts in miniature swine is uniformly induced across a two-haplotype class I plus minor histocompatibility antigen disparity by a 12-day course of cyclosporine. Recent studies have demonstrated that the thymus is essential for rapid and stable tolerance induction, because either prior thymectomy or a series of thymic biopsies induce a spontaneously reversible rejection crisis after the 12-day course of cyclosporine. The present study examined the peripheral cellular mechanisms of tolerance by analyzing cytotoxic effector pathways in peripheral blood lymphocytes (PBL) of tolerant animals. METHODS: The phenotype and cytotoxic T lymphocyte response of alloantigen-activated PBL cultures using cells from a series of tolerant animals with stable renal function (no thymic manipulation), or during a rejection crisis (induced by thymic biopsies), were studied. The in vitro findings were correlated with the in vivo clinical course of experimental animals. RESULTS: The data demonstrated that in vivo and in vitro tolerance was associated with a specific deficiency of interleukin-2 receptor (IL-2R) alpha-chain up-regulation on CD8 single-positive (SP) T cells expressing high levels of CD8 (CD8high) when PBL from tolerant animals are stimulated with donor class I alloantigen. Stimulation by third party class I alloantigen, or by donor antigen during a rejection crisis, produced efficient cytotoxic T lymphocyte responses and expression of IL-2Ralpha on CD8high SP cells. CONCLUSION: Antigen-specific regulation of the IL-2Ralpha expression on CD8high SP PBL is a principal event associated with and potentially involved in the mechanism of tolerance in this preclinical large animal model.

Animals↗
PubMed1999

Role of the thymus in transplantation tolerance in miniature swine: II. Effect of steroids and age on the induction of tolerance to class I mismatched renal allografts.

BACKGROUND: Recent studies in young (5-7 months) miniature swine have demonstrated that the thymus is involved in the rapid induction of stable tolerance to class I mismatched renal allografts after a 12-day course of Cyclosporine (CyA). Because both steroids and age are known to influence the structure and function of the thymus, we have now studied the effects of these two parameters on tolerance induction in this model. MATERIALS AND METHODS: In young swine, the administration of methylprednisolone (MP) during the standard tolerance-inducing regimen (a 12-day course of CyA) produced severe renal dysfunction and acute cellular rejection histologically. However, the renal allografts recovered and were accepted for >100 days with histological evidence of chronic rejection. To test the effect of age, two relatively old swine (55 and 71 months) received transplants of class I mismatched renal allografts and the standard 12-day course of CyA. One animal rejected the allograft acutely on postoperative day 22, and the second also rejected, but more slowly, with manifestations of chronic rejection. CONCLUSION: These findings suggest that both MP and old age interfere with the induction of stable tolerance in a fashion similar to the previously described effect of thymectomy. These results may have important implications for the mechanism of thymic-dependent tolerance, for the use of steroids in clinical protocols for the induction of allograft tolerance, and for the application of such protocols to adult patients.

Animals↗
PubMed1999

The effect of thymectomy on tolerance induction and cardiac allograft vasculopathy in a miniature swine heart/kidney transplantation model.

BACKGROUND: We have previously demonstrated that MHC class I disparate hearts transplanted into miniature swine treated with a short course of cyclosporine developed florid cardiac allograft vasculopathy (CAV) and were rejected within 55 days. However, when a donor-specific kidney is cotransplanted with the heart allograft, recipients become tolerant to donor antigen and accept both allografts long-term without the development of CAV. In the present study, we have investigated the role of the host thymus in the induction of tolerance and prevention of CAV in heart/kidney recipients. METHODS: Total thymectomies were performed in six animals (postoperative day [POD]-21), which on day 0 received either an isolated MHC class I disparate heart allograft (n=3) or combined class I disparate heart and kidney allografts (n=3), followed in both cases by a 12-day course of cyclosporine (POD 0-11). Graft survival and the development of CAV in these thymectomized recipients were compared to the same parameters in non-thymectomized, cyclosporine-treated recipients bearing either class I disparate heart allografts (n=5) or heart and kidney allografts (n=4). RESULTS: In the group of animals bearing isolated class I disparate heart allografts, the thymectomized recipients rejected their allografts earlier (POD 8, 22, 27) than the non-thymectomized recipients (POD 33,35,45,47,55). The donor hearts in both the thymectomized and non-thymectomized animals developed florid CAV. In the group of animals bearing combined class I disparate heart and kidney allografts, the nonthymectomized recipients accepted both donor organs long term with no evidence of CAV. In contrast, none of the thymectomized heart/kidney recipients survived >100 days, and they all developed the intimal proliferation of CAV. CONCLUSION: Thymic-dependent mechanisms are necessary for the induction of acquired tolerance and prevention of CAV in porcine heart/kidney recipients.

Animals↗
PubMed2001

Induction of transplantation tolerance with a short course of tacrolimus (FK506): I. Rapid and stable tolerance to two-haplotype fully mhc-mismatched kidney allografts in miniature swine.

BACKGROUND: Inbred miniature swine provide a large animal model in which the effects of selective major histocompatibility complex (MHC) matching can be reproducibly studied. We have previously demonstrated that although a 12-day course of cyclosporine uniformly induces tolerance to class I-mismatched renal allografts, it does not induce tolerance across full MHC barriers. In this study, we assessed whether and at what dose tacrolimus might permit allografts to induce tolerance across different MHC barriers. METHODS: Recipients of MHC disparate renal allografts were treated with a 12-day course of tacrolimus by continuous intravenous infusion. Groups were divided as follows: (1) class I-mismatched kidneys with 0.3 mg/kg/day tacrolimus (n=3); (2) fully MHC-mismatched kidneys with 0.3 mg/kg/day tacrolimus (n=2); and (3) fully MHC-mismatched kidneys with 0.12-0.16 mg/kg/day tacrolimus (n=4). RESULTS: In groups 1 and 2, recipients with tacrolimus levels of 45-80 ng/ml accepted renal allografts long-term with stable renal function. Donor-specific hyporesponsiveness was demonstrated by cell-mediated lymphocytotoxicity and mixed lymphocyte response, and subsequent donor-matched grafts were also accepted, without further immunosuppression (n=4), confirming systemic tolerance. In group 3, recipients that achieved tacrolimus levels of 35 ng/ml (n=2) accepted their grafts without chronic changes, whereas recipients with levels of 20-26 ng/ml (n=2) developed chronic allograft glomerulopathy, suggesting 35 ng/ml as the threshold blood level for tolerance induction. In vitro assays demonstrated that peripheral blood lymphocytes from tolerant animals produced inhibitory cytokines, suggesting the involvement of regulatory mechanisms. CONCLUSIONS: To our knowledge, this study represents the first demonstration of the induction of transplant tolerance across a two-haplotype full MHC barrier with a short course of immunosuppression in a large animal model. These studies may also have clinical applicability, because the time course required to induce tolerance was sufficiently short that the high drug levels required might be expected to be tolerated clinically with only transient toxicity.

Animals↗
PubMed2001

Skin-specific alloantigens in miniature swine.

BACKGROUND: The acceptance of skin allografts has historically been among the most challenging problems in the field of transplantation, attributed, at least in part, to the existence of antigens expressed by skin but not by other tissues. Many studies have suggested the existence of skin-specific antigens in rodents, but data in large-animal models are more limited. METHODS: We have recently developed protocols for attaining stable mixed hematopoietic chimerism in miniature swine, using MHC-matched donors and recipients. We have now assessed tolerance to donor-derived skin and cardiac allografts in these chimeric animals. RESULTS: Skin-graft rejection was seen in four of six animals receiving skin grafts taken from the respective hematopoietic donors. In the other two animals, donor-derived skin grafts survived indefinitely. No cardiac-allograft rejection was observed in mixed-chimeric animals that received heart transplants from their hematopoietic donors, even in animals that had already rejected skin allografts from the same donors. In all animals assessed, in vitro hyporesponsiveness to donor hematopoietic cells persisted. CONCLUSION: These findings support the concept that skin expresses immunogenic alloantigens that either are not expressed or are not immunogenic in cardiac or hematopoietic tissue.

Animals↗