Use Of Total Lymphoid Irradiation Research Articles

Beyond cancer treatment - a review of total lymphoid irradiation for heart and lung transplant recipients.

Immunosuppressive drugs used in the management of heart and lung transplants have a large monetary and quality of life cost due to their side effects. Total lymphoid irradiation (TLI) is one method of minimising the need for or replacing post-operative immunosuppressive drugs. A literature review was conducted on electronic databases using defined search terms. The aim was to establish the indications for the use of TLI, its advantages and disadvantages and the weaknesses associated with the methods used in related research. Eight articles were located that focused on TLI usage in combating organ rejection. These studies identified that the use of TLI resulted in a reduction in early rejection. One study reported a drop in rejection episodes from 0.46 to 0.14 episodes per patient per month once the TLI was complete. While the short-term prognosis is excellent, the long-term outlook is less positive with an increased risk of organ rejection and myelodysplasia 3.5 years post-TLI. This review reminds us that radiation therapy (RT) is not exclusively indicated for cancer treatment. While TLI cannot replace immunosuppressive drug therapy, it can offer a treatment option for people that cannot tolerate immunosuppressive drugs, or when conventional anti-rejection treatment is no longer viable. Reported long-term complications suggest that TLI should be used with caution. However, this modality should not be overlooked in cases of chronic rejection. Further research is required to establish the efficacy of RT in the treatment of transplant patients who are unsuitable for drug-based anti-rejection therapies.

Induction of tolerance in clinical kidney transplantation

Induction of donor-specific tolerance has been an ultimate goal in organ transplantation. Although numerous regimens for the induction of allograft tolerance have been developed in rodents, their application to primates has been limited. The approaches that have been successfully applied in primates can be divided into (i) use of total lymphoid irradiation, (ii) costimulatory blockade, (iii) profound depletion of recipient T cells, (iv) infusion of regulatory cells and (v) donor bone marrow (DBM) infusion/transplantation. Among these approaches, successful allograft tolerance has been achieved in clinical kidney transplantation using DBM transplantation.

Donor bone marrow transplantation as an approach to tolerance induction for clinical kidney transplantation

Purpose of review Despite recent improvements of short-term results in clinical organ transplantation, long-term results are still not satisfactory. To further improve long-term results, clinical trials for the induction of tolerance are underway. This review summarizes the background and results of clinical tolerance induction trials, especially those using donor bone marrow infusion/transplantation. Recent findings The strategies for tolerance induction that have been successful in nonhuman primates can be categorized as follows: use of total lymphoid irradiation; costimulatory blockade; profound depletion of recipient T cells; infusion of regulatory cells; and donor bone marrow infusion/transplantation. Among these approaches, however, induction of mixed chimerism through donor bone marrow transplantation is the only approach that has been successfully translated to clinical kidney transplantation to date. Summary Induction of tolerance in clinical kidney transplantation has been achieved via a mixed chimerism approach. Better understanding of the mechanisms of tolerance and improvements in the morbidity of conditioning regimens for tolerance induction will undoubtedly be important in bringing this modality to wider clinical applications.

Approaches to transplantation tolerance in humans.

Although transplantation tolerance to organ allografts has been achieved using a wide variety of immunologic interventions in laboratory animals, few tolerance induction protocols with complete immunosuppressive drug withdrawal have been tested in humans. Preclinical and clinical studies of the use of total lymphoid irradiation for the induction of chimeric and nonchimeric tolerance are summarized here.

Surveillance transbronchial lung biopsies: Implication for survival after lung transplantation

Objectives: We wished to determine whether early rejection after lung transplantation as assessed by surveillance transbronchial biopsy predicts for survival. Methods: Between 1990 and 1997, 96 consecutive patients had lung transplantation: 89 had a minimum 1-month follow-up. For 71 consecutive patients we have 1-year follow-up and for 69 patients we have the results of the first 3 biopsies. Cytomegalovirus status, bronchiolitis obliterans prevalence, and use of total lymphoid irradiation are noted. Biopsies were done at 1 week and 1, 3, and 6 months. Standard immunosuppression consisted of induction antilymphocyte globulin and high-dose methylprednisolone induction for 1 week and standard maintenance triple therapy. Acute rejection treatment was with pulse methylprednisolone. Bronchiolitis obliterans syndrome was treated with total lymphoid irradiation and a change to tacrolimus and mycophenolate. Blinded grading using International Society for Heart and Lung Transplantation classification was done retrospectively. Results: Survival at 1 month and 1, 2, and 3 years for the 96-patient cohort with 1-year follow-up was 93%, 74%, 62%, and 56%. Survival was not significantly different for subsets with rejection on any combination of the first 3 biopsies (1/3, 2/3, 3/3) or absence of rejection on the first 3 biopsies. Ninety-one positive biopsy results were graded. Eighteen of 71 patients had one or more moderate or severe rejection episodes without survival difference relative to the others. There was no statistically significant association between acute rejection on the first 3 surveillance biopsy results and bronchiolitis obliterans. Conclusions: Intensive induction and maintenance immunotherapy with surveillance transbronchial biopsies and aggressive treatment of acute rejection is associated with a survival similar to that of patients without early acute rejection. This regimen appears to uncouple the association between early acute rejection and bronchiolitis obliterans. Further study may elucidate this mechanism. (J Thorac Cardiovasc Surg 2000;119:27-38)

Total Lymphoid Irradiation for Refractory Acute Rejection in Heart-Lung and Lung Allografts

Persistent or recurrent acute allograft rejection (AR) refractory to high-dose steroid therapy can adversely affect long-term outcomes of heart-lung (HLT), bilateral-lung (BLT), and single-lung (SLT) transplantations. The use of total lymphoid irradiation (TLI) for the management of refractory acute AR in six transplant recipients (two men, four women; mean age, 29.8 +/- 3.8 years) is detailed. There are two HLT (primary pulmonary hypertension [PPH], cystic fibrosis [CF]), 1 BLT (pulmonary hypertension postventricular septal defect repair), and 3 SLT (sarcoid, PPH, congenital heart disease with atrial septal defect) recipients. Refractory AR is defined as persistent rejection unresponsive to high-dose steroid therapy in all cases. The BLT and SLT recipients had at least two moderate and one mild AR events per patient. The HLT recipients had at least two moderate acute heart and one severe and one mild asynchronous acute lung rejection events per patient. A total of 800 cGy of total lymphoid irradiation (TLI) was administered over a 5-week period. Mild and transient leukopenia was the only observed side effect. The patient with PPH received TLI 313 days after HLT for recurrent AR at another institution and died of ARDS 4 weeks after completing TLI. The patient with CF received TLI 707 days after HLT and died 457 days after TLI of severe obliterative bronchiolitis (OB) with multiorgan failure. The patient with BLT received TLI 176 days after transplant and died 372 days after TLI of respiratory failure related to severe rejection. One patient with SLT received TLI 78 days after transplant and died 679 days after TLI of severe acute AR. The two remaining patients with SLTs have been free from acute AR for more than 4 years. The patient with sarcoidosis received TLI 37 days after SLT following a clinical rejection event and two severe acute AR events. He is alive with normal lung function 5 years later. The patient with PPH received TLI 108 days after SLT following three moderate acute AR events and is alive with stable OB 4 years later. These limited preliminary results suggest that TLI has merit for the treatment of intractable acute AR following HLT and lung transplantation.

Management of renal hypertension in children with Takayasu's arteritis using renal autografting or allograft transplantation in selected circumstances and total lymphoid irradiation

In a decade from 1980, 11 children aged 3 to 11 years presented with Takayasu's arteritis (TA). All were severely hypertensive. Operative correction was offered to 10 of 11 children presenting with renovascular hypertension (RVH) including cardiac failure alone in 1 and both renal and cardiac failure in 8, a result of TA involving renal arteries by stenosis or occlusion. Nine patients had renal autotransplantation to an heterotopic site in the pelvis. Seven of 12 kidneys were salvaged by autotransplant with relief of RVH. Renal artery stenosis was successfully corrected by this procedure in 5 patients. Autotransplantation failed in 4 patients, 1 of whom subsequently had a successful allograft transplant. One patient was treated primarily by cadaver allograft transplantation. One patient whose autotransplant failed had a functioning contralateral kidney and is well with controlled RVH. One patient died prior to any treatment. Patient survival improved with the use of total lymphoid irradiation in the most recent 7 patients.

Successful cardiac xenogeneic transplantation in primates using total lymphoid irradiation

Combined total lymphoid irradiation (TLI) and cyclosporine (CyA) dramatically prolong cardiac xenografts in small animals. In order to evaluate this immunosuppressive regimen in primates, heterotopic cardiac cervical xenografts were implanted in a monkey-to-baboon model. The following groups evolved: group 1 (n = 2) control, no immunosuppression; group 2 (n = 4) CyA and steroids; group 3 (n = 2) preoperative TLI (800 rad total); group 4 (n = 4) TLI combined with CyA and steroids as in groups 2 and 3. Complement-dependent cytotoxicity, mixed lymphocyte culture, cell mediated cytotoxicity as well as myocardial biopsies were periodically monitored. A Muga scan was performed at 1 year posttransplant to assess ventricular function. Cardiac xenograft survival was best in group 4 animals (108, 184, 480, 540 days) compared with 5 and 7 days in the control group. In group 2, graft survival was 13, 17, 18 and 63 days. TLI alone prolonged survival up to 28 and 29 days. Hemorrhage and myocyte necrosis were seen in all rejected grafts of group 1, 2 and 3 animals. Mononuclear cell infiltrate and fibrosis were present in group 4 grafts at rejection. High antibody titers (1:256 to 1:512) were detected at rejection only in group 1, 2 and 3 animals. This suggests that the combined use of TLI and CyA substantially prolongs xenograft survival in a primate model by preventing early antibody-mediated rejection as well as by limiting cellular response.

Irradiation for xenogeneic transplantation

Xenogeneic transplantation (XT) is the transplantation of organs or tissues from a member of one species to a member of another. Mammalian species frequently have circulating antibody which is directed against the foreign organ irrespective of known prior antigen exposure. This antibody may lead to hyperacute rejection. There is no reliable means to avert hyperacute rejection once it ensues so efforts must be directed towards eliminating the pre-existing antibody. In those species in which hyperacute rejection of xenografts does not occur, cell-mediated rejection, similar to allograft rejection, may occur. It is in the prevention of this latter form of rejection that radiation is most likely to be beneficial in XT. Both total lymphoid irradiation (TLI) and selective lymphoid irradiation (SLI) have been investigated for use in conjunction with XT. TLI has contributed to the prolongation of pancreatic islet-cell xenografts from hamsters to rats. TLI has also markedly prolonged the survival of cardiac transplants from hamsters to rats. A more modest prolongation of graft survival has been seen with the use of TLI in rabbit-to-rat exchanges. Therapy with TLI, cyclosporine, and splenectomy has markedly prolonged the survival of liver transplants from hamsters to rats, and preliminary data suggest that TLI may contribute to the prolongation of graft survival in the transplantation of hearts from monkeys to baboons. SLI appears to have prolonged graft survival, when used in conjunction with anti-lymphocyte globulin, in hamster-to-rat cardiac graft exchanges. The current state of knowledge of the use of irradiation in experimental XT is reviewed.

The influence of dose and dose rate of total lymphoid irradiation in the rat cardiac allograft model

Immunosuppression generated by total lymphoid irradiation (TLI) may be of use in solid organ transplantation. We have investigated the use of TLI in the rat cardiac allograft model. Lewis rats received TLI from a cobalt-60 machine. The daily dose was 1.25 Gy and treatments were administered 4 days per week. We performed experiments to assess the effect of dose rate upon graft survival. The dose rate was varied by changing the source to animal distance and by using a lead attenuator. Cardiac allografts from each ACI donor rat were transplanted to the recipient Lewis rat's abdomen utilizing microvascular surgical technique. Heart graft survival times (GST) were monitored by direct palpation of the cardiac impulse. Immune function was measured by an activity index of the mixed lymphocyte reaction. In the absence of any immunosuppression there was a mean GST of 6.9 +/- 0.3 days. When a graft was placed the day following completion of TLI, there was an increase in GST as the total TLI dose was increased. Mean GST (+/- S.E.) following 5, 10, and 15 Gy were 12.3 +/- 1.3, 14.5 +/- 1.3, and 25.5 +/- 1.1 days, respectively. Following 20 Gy, GST decreased because of irradiation induced pulmonary toxicity and host death. When 3.5 weeks were allowed to elapse between the completion of TLI and transplantation, GST were less than those seen with equivalent doses of TLI and early transplantation. Mean GST following 5, 10, and 15 Gy and a delayed transplant were 7.2 +/- 0.1, 10.7 +/- 1.2, and 19.0 +/- 3.5 days, respectively. We tested the effect of dose rate upon GST.(ABSTRACT TRUNCATED AT 250 WORDS)

Preoperative preparation of high-risk, specifically hyperimmunized canine renal allograft recipients with total-lymphoid irradiation and cyclosporine.

Hyperimmunized subjects are a particularly high-risk and rapidly growing group in the patient population awaiting renal transplantation. In a search for methods designed to ameliorate the prognosis in such cases, dogs of defined DLA genotype were sensitized with DLA incompatible skin allografts and injections of buffy coat. Each recipient was challenged with a renal allograft bearing the same DLA incompatibilities. Five dogs received kidney transplants, without any other treatment, and rejected their transplants at 2.5, 4, 5, 6, and 6.5 days, respectively. Another four dogs were given a 9-11-week course (1760 +/- 35 cGy) of total-lymphoid irradiation (TLI), followed by rabbit antithymocyte globulin (ATG); these animals rejected their renal allografts at 7, 8, 14, and 17 days, respectively. Five other dogs were treated with TLI and received cyclosporine (CsA) and methylprednisolone (MPd) daily until graft rejection. Their renal allografts survived for 7.5, 8.5, 20, 62, and 227 days, respectively. Renal allografts placed in normal recipients under the same conditions of donor-recipient DLA incompatibility had a mean survival time of 12.4 days (range: 10-18 days). At the time of transplantation, the specific anti-DLA antibody titers in the recipients were 81 to 243 in the untreated dogs; 27 to 81 in the TLI-ATG-treated group, and 3 to 243 in the TLI-CsA/MPd-treated group. The titers fell within 24-48 hr after renal transplantation, to 3 to 81 in the untreated sensitized dogs; they were 3 to 9 in the TLI-ATG-treated group, and were 9 to 243 in the TLI-CsA/MPd treated group. The cytotoxic antibody titers reached postoperative peaks of 6500 to 200,000 in the untreated dogs; 729 to 6500 in the TLI-ATG-treated dogs, and 243 to 6500 in the TLI-CsA/MPd-treated recipients. The combined use of TLI and CsA/MPd can significantly inhibit the capacity of immunized recipients to muster a secondary humoral response to the DLA antigen(s) used in the sensitization process; such treatment also abrogates the ability of the recipients to reject renal allografts bearing the same DLA specificities in accelerated fashion. This effect of TLI and cyclosporine may be of relevance to current severe problems in high-risk hyperimmunized human renal transplant candidates.

Efficacy and side effects of total lymphoid irradiation (TLI) in severe rheumatoid arthritis and lupus nephritis. Risk of malignancy after the use of TLI in Hodgkin's disease with and without chemotherapy

Efficacy and side effects of total lymphoid irradiation (TLI) in severe rheumatoid arthritis and lupus nephritis. Risk of malignancy after the use of TLI in Hodgkin's disease with and without chemotherapy

The use of total lymphoid irradiation for allogeneic bone marrow transplantation in animals and man

Based on the previous experience in experimental animals and man, it may be concluded that TLI provides a useful method of immunosuppression and, under certain conditions, induces permanent and specific tolerance to BM and organ allografts, even across major histocompatibility barriers. Experience regarding the applicability of TLI to clinical BMT for malignant as well as nonmalignant disorders, as an adjunct to other immunosuppressive treatment modalities, is preliminary, but appears encouraging. Further studies are necessary to assess the relative advantages over the alternative methods of immunosuppression currently available.

Resistance to mycobacteria in mice treated with fractionated total lymphoid irradiation (TLI) and in mice reconstituted with allogeneic bone marrow cells following radiotherapy

The increased clinical use of total lymphoid irradiation (TLI) as an immunosuppressive adjunct in transplantation suggested the need for determining the effects of TLI on the in vivo susceptibility of animals to infections controlled by cell-mediated immunity. TLI-treated, TLI-treated and splenectomized, and chimeric mice prepared with TLI were inoculated in the hind foot pad with Mycobacterium marinum or Mycobacterium leprae. Although M. marinum organisms multiplied in greater numbers in the TLI mice, ultimately they were destroyed as effectively in TLI mice as in the non-irradiated control mice. M. leprae multiplied at the same rate and to the same maximum in TLI mice as in controls. Mice previously challenged with M. marinum in one hind foot pad, and challenged subsequently with the same organism in the opposite hind foot pad, showed a solid immunity against this reinfection. It appears that upon recovery from the immediate effects of radiotherapy TLI-treated mice are able to mount an effective immune response to experimental infection with M. marinum and M. leprae.

Use of total lymphoid irradiation (TLI) in studies of the T cell-dependence of autoantibody production in rheumatoid arthritis.

The effect of total lymphoid irradiation (TLI) on T cell-dependent and -independent humoral immune responses was studied in patients with intractable rheumatoid arthritis (RA). The serum levels of several autoantibodies and of antibodies to diphtheria (DT) and tetanus (TT) toxoids and to pneumococcal polysaccharide (PPS; 12 antigenic types) were studied before and after TLI. In addition, the patients were given a booster injection of DT and TT and a single injection of pneumococcal vaccine after radiotherapy. Antibody levels to DT and TT decreased about twofold after TLI and did not rise significantly (p greater than 0.05) after a booster injection. However, there was no reduction in antibody levels to PPS after TLI, and a significant rise in titers was observed after a single vaccination (p less than 0.01). The serum levels of rheumatoid factor (RF), anti-nuclear antibody (ANA), and granulocyte associated IgG rose slightly after TLI. Thus, the autoantibodies and antibodies to polysaccharides appear to be relatively independent of helper T cell function, which is markedly reduced after TLI. On the other hand, antibodies to protein antigens such as DT and TT appear to be more closely dependent upon T helper function in man, as has been reported in rodents. The findings suggest that T cell-independent autoantibody responses alone do not maintain the joint disease activity in RA, because improvement in joint disease after TLI has been reported.

Arthritis patients get long-term help from total lymphoid irradiation

Total lymphoid irradiation (TLI)—a technique developed at Stanford University Medical Center, California, originally for treatment of stage III Hodgkin's disease—is yielding such "encouraging" results in patients with intractable rheumatoid arthritis that its application to a broader range of autoimmune diseases and organ transplantation is now being investigated. In a keynote address at the recent meeting of the American Society of Therapeutic Radiologists (ASTR) in Orlando, Fla, Henry S. Kaplan, MD, director of the Cancer Biology Research Laboratory at Stanford, said that although use of TLI for autoimmune disease is still very much investigational, it would appear, "based on our limited experience so far, that this will become a new treatment for patients with very far advanced and crippling autoimmune disease." Still, he emphasized the experimental nature of this work, telling the audience: "We would be quite alarmed if there were any widespread move to adopt this as a treatment for

Use of total lymphoid irradiation in transplantation of rat fetal pancreases.

The objective of this study was to determine the effectiveness of total lymphoid irradiation (TLI) treatment of the induction of unresponsiveness to allogeneic whoie fetal pancreas tissues, which are highly immunogenic (control survival times in three combinations: <10 days). Streptozotocin-diabetic Lewis male rats were irradiated 4–5 times a week with a daily dose of 200 rads under a lead shield covering the skull, lungs, hind legs, pelvis, and tail. The spleen, thymus, and major lymph nodes were exposed to radiation. When the desired total TLI dose was reached, the rats were injected with 1–3 × 108 donor-type aduit bone marrow cells within one day after TLL, followed by fetal pancreas transplants under the kidney capsule between 1 and 35 days after TLI. Three strain combinations with immunogenetic barriers ranging from moderate (non-Rt1) to strong (Rt1) were used to determine a minimum effective dose for the permanent acceptance of pancreas allografts. Fischer → Lewis fetal pancreases identical at Rt1 but differing at multiple non-Rt1 loci were accepted permanently in the recipients who were treated with 1200 rads TLI and 108 donor bone marrow cells. Diabetes was permanently reversed or significantly improved. A minimum effective TLI dose in this combination was found to be 1000 rads. (Buffalo × Lewis)F1 → Lewis fetal pancreas grafts across strong Rt1 barriers required at least a total TLI dose of 2600 rads, when semiallogeneic F1 bone marrow cells were used. A higher dose (3000 rads) was required, when 1–3 × 108 of fully allogeneic Buffalo bone marrow ceils were grafted. Even then, only a part of the group of treated Lewis became unresponsive to donor tissues. Removal of the pelvic shield, however, resulted in consistent development of a high percentage of donor bone marrow chimera and permanent acceptance of allografts in Buffalo or F1 × Lewis combinations. This procedure exposed the whole pelvic area and part of the femur along with the portions exposed by the complete lead shield procedure. Donor-type bone marrow grafting, in addition to TLI, was essentiai for permanent acceptance of allografts.

The use of total lymphoid irradiation (TLI) as immunosuppressive therapy for organ allotransplantation and autoimmune diseases.

Radiation induced alterations in the number and immune functions of peripheral blood lymphocytes have recently been described in patients treated with fractionated localized or extended field radiotherapy for carcinoma of the breast, lung, bladder uterine cervix, prostate, testicular tumors, head and neck tumors, Hodgkin's disease, and in children receiving prophylactic craniospinal radiation for acute lymphoblast leukemia. Most studies have demonstrated an acture peripheral blood lymphocytopenia and varying degrees of suppression of immune functions such as the in vitro blastogenic responses to stimulation with lectins or with allogeneic lymphocytes in the mixed lymphocyte reaction (MLR), and in the in vivo delayed hypersensitivity responses to dinitrochlorobenzene (DNCB) and intradermally injected bacterial and fungal antigens. Most studies have also shown various degrees of recovery of the above immune functions within the first few years after completion of treatment.