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It has been suggested that elderly people are more susceptible to infectious diseases because of immunosenescence. The well-described transient immunosuppressive effect of exercise may increase health risks in such populations. Although resistance training has been recommended to older individuals, little is known regarding its acute effects on immune indexes. This study examined the acute effects of resistance exercise sessions performed at different intensities (50 vs. 80% of one-repetition maximum [1RM]) on salivary immunoglobulin A (IgA), total leukocytes, lymphocytes and their subsets, and the cortisol levels of older women. Fifteen physically independent elderly women (mean age = 67.5 +/- 3.9 years) underwent, in a randomized manner, two experimental sessions comprising resistance exercise for the major muscular groups or one control session without exercise. Session 1 consisted of two sets of 13 repetitions at 50% 1RM, whereas session 2 consisted of two sets of eight repetitions at 80% 1RM. Blood and saliva samples were collected at rest, immediately after, and at 3 and 48 hours after the completion of the sessions. Blood cortisol, total leukocytes, lymphocytes and their subpopulations, and salivary IgA were measured by standard techniques. Overall, resistance exercise sessions failed to provoke significant decline on the examined immune function indexes. Instead, resistance exercise sessions induced significant elevation in salivary IgA levels, but this was not observed after the control session. Also, experimental sessions did not induce significant elevations in blood cortisol. It was concluded that resistance exercise sessions performed at 50 or 80% of 1RM do not present suppressive effects on the studied immune parameters. Conversely, a transient elevation was observed in salivary IgA levels, which requires support in future investigations. Taken together, the observed results suggest that elderly women can engage in resistance training programs without negative acute effects on the studied parameters of the immune system.

Objective: To review the specific infections common in pediatric burns, including their categorization, diagnosis, and treatment. Design: Review of the literature and expert opinion. Results: Children with serious burns are prone to a host of septic complications. This proclivity to infection is secondary to the immunosuppressive effect of burn injury, the loss of the skin and mucosal physical barriers, and the requirement for invasive support devices. Conclusion: Sepsis is common in the pediatric burn patient and can markedly increase morbidity and mortality. Anticipation, prompt diagnosis of infection, and effective therapy can result in successful outcomes for many of these children.

The authors' aim was to evaluate the efficacy of immunosuppression with monoclonal anti-CD40 ligand antibodies (aCD40L) or nonspecific polyclonal intravenous immunoglobulin (IVIG) in the pig-to-rat islet xenotransplantation model.Fetal porcine islet-like cell clusters were transplanted under the kidney capsule of nondiabetic rats. All antibodies were administered alone or in combination with cyclosporine A (CsA). In addition, some animals were administered antibodies plus tacrolimus (TAC) or sirolimus (SIR). Twelve days after transplantation, islet xenograft survival and rejection were evaluated using immunohistochemistry.aCD40L plus CsA had a pronounced inhibitory effect on islet xenograft rejection for up to 12 days after transplantation. Unexpectedly, treatment with a monoclonal control antibody (anti-keyhole limpet hemocyanin [aKLH]) plus CsA had a similar inhibitory effect. Furthermore, a similar inhibition of islet xenograft rejection was observed also in animals administered IVIG plus CsA. Monotherapy with aCD40L, aKLH, IVIG, or CsA had no effect on the rejection process. Also, when aCD40L or aKLH was administered together with TAC, islet xenograft rejection was inhibited. There was no marked difference compared with rats treated with aCD40L or aKLH and CsA. Immunosuppression with aCD40L or aKLH in combination with SIR also inhibited pig-to-rat islet xenograft rejection, but the protective effect was not as pronounced.Immunosuppression with high doses of antibodies, monoclonal or polyclonal, in combination with CsA or TAC inhibits pig-to-rat islet xenograft rejection. No specific effect of co-stimulatory blockade with aCD40L could be observed. Instead, the results indicate a nonspecific immunosuppressive effect of high doses of antibodies in this model.

From a surgical point of view, one of the most important consequences of blood transfusion is the immunosuppressive effect and its possible link to postoperative infectious complications and cancer recurrence. The underlying mechanism of transfusion-induced immunosuppression seems to be mediated by transfusion with leukocytes. In prospective randomized trials, therefore, efforts have been made to control the immunosuppressive effect of allogeneic blood transfusion by the use of leukocyte-reduced blood. Only one prospective clinical trial has asserted the effect of leukocyte reduction on cancer recurrence, and no benefit to outcome was found. In four big randomized, prospective clinical trials, allogeneic blood transfusion was associated with significantly increased rates of postoperative infections, and the use of leukocyte reduction was found to have striking benefits in three of the trials, with a several-fold reduction in rates of morbidity and mortality.

Despite advances in prophylaxis and treatment, cytomegalovirus (CMV) infection remains a significant problem in the solid-organ transplant recipient. In addition to the clinical manifestations of CMV infection, there is also the immunosuppressive effect of CMV, which confers increased risk for fungal and other opportunistic infections. In reference to heart transplant recipients, the possible connection between CMV infection and rejection or CMV infection and allograft vasculopathy are areas of active research. Recent diagnostic advances, such as the CMV antigenemia assay and CMV-DNA detection by polymerase chain reaction or direct hybrid capture, have enabled early detection and monitoring of CMV infection and have raised the question of the implications of asymptomatic viremia. A wide variety of prophylactic strategies have been evaluated in heart and other solid-organ transplant recipients, including antiviral agents, globulin preparations, combinations of these therapies, and pre-emptive treatment strategies based on early detection or identification of a high-risk subset of patients. Many of these regimens have demonstrated efficacy in certain groups of patients, but a consensus has yet to emerge in terms of a single preferable strategy. Future advances on the horizon include the development of newer antiviral agents and a vaccine.

The efficacy of rapamycin (RAPA) was tested on small bowel transplantation in the mouse and compared with cyclosporine (CsA). Four groups were involved, each one included three combinations (n > or = 6) for evaluation of host-versus-graft (HVG, C57BL/6 X BALB/c F1 (CB6F1)-to-BALB/c), graft-versus-host (GVH, BALB/c-to-CB6F1), and combined HVG and GVH responses (C57BL/6-to-BALB/c). Grafts were transplanted to recipients heterotopically. Groups were as follows: group 1: naive controls; groups 2 and 3: recipient mice treated with RAPA 2 mg/kg/day and 4 mg/kg/day orally for 14 days, respectively; group 4: recipient mouse treated with CsA 4 mg/kg/day orally for 14 days. In the HVG model, the mean survival time (MST) of recipients was significantly longer in group 2 (32.9 +/- 17.7 days, P=0.006), group 3 (32.7 +/- 10.4 days, P=0.0001), and group 4 (37.9 +/- 11.8 days, P=0.0001), compared with naive controls in group 1 (8.5 +/- 1.6 days). In the GHV model, the MST of recipients in group 2 (41.8 +/- 19.9 days, P=0.002), group 3 (48.2 +/- 21.4 days, P=0.001) and group 4 (56.5 +/- 30.6 days, P=0.003) were significantly prolonged compared with control group 1 (8.5 +/- 1.6 days). In combined HVG and GVH responses, MST of recipient in group 2 (20.9 +/- 4.9 days, P=0.0001), group 3 (27.0 +/- 4.3 days, P=0.008), and group 4 (35.2 +/- 23.9 days, P=0.0001) were also significantly longer than that in controls (6.9 +/- 1.4 days), but in all three combinations, there were no statistically significant differences between groups 2 and 3, groups 2 and 4, or groups 3 and 4 (P>0.05). RAPA is a potent immunosuppressant able to significantly prolong small bowel allograft survival in mice using a short-term treatment. There is no statistically significant difference in recipient survival between low and high doses of RAPA treatment and the CsA standard dose used in this study.

The effect of deoxymethylspergualin (MeDSG) on in vitro human lymphocyte response was assessed in comparison with FK506 and cyclosporine. Peripheral blood mononuclear cells from normal human volunteers were used for assay of mixed lymphocyte reaction, cell mediated lympholysis, and blastogenesis by PHA, IL-2, and OKT3. MeDSG suppressed only allogeneic stimulation (MLR and CML) and IL-2-induced blastogenesis, not PHA- or OKT3-induced blastogenesis, although the other immunosuppressive agents showed some suppres-sive effect for all assays. A kinetic study of MLR showed that the suppressive activity did not decrease even when MeDSG was added at day 3 or day 4. The other agents, however, showed a weak suppressive effect when added at a later phase of MLR.

Unlike skin allografts in rats, accelerated rejection of second-set kidney allografts was a rare occurrence. Host reactivity was generally suppressed as a consequence of first-set kidney rejection, resulting in prolonged survival of a second-set kidney bearing the same alloantigens. Three variables with potentially important clinical implications were critical for induction of extended survival of the second kidneys: (1) Longer first-set kidney retention or sensitization periods promoted prolonged second-set allograft survival; the longer the period (tested up to 50 days), the greater was the observed immunosuppression. (2) Shorter intervals between first set removal and second-set grafting greatly prolonged second-set survival times; the shorter the interval, the greater the immunosuppressive effect. The optimal timing for facilitation of second kidney survival may be assumed as the time of first kidney removal. (3) Lesser or weaker histoincompatibility of the second kidney clearly promoted prolonged or indefinite survival. Thus, the second kidney from semiallogeneic F1 hybrids survived far longer than fully allogeneic parental kidneys. Prolongation of second-set F1 kidney survival could be achieved under less strict conditions. Spleen lymphocytes from second kidney recipients showed suppressed alloreactivity in the popliteal lymph node graft-versus-host (GVH) assay. Prolonged survival of repeated renal allografts is attributable to intervention of an active immunoblocking process rather than acquired tolerance.

These studies were performed to evaluate the immunosuppressive effect of concanavalin A (ConA) in monkeys. Bonnet monkeys (Macaca radiata) weighing between 2.5-3.5 kg were used. Following the exchange of full thickness skin allografts in randomly selected animals, gross and histopathological studies of the rejection reaction were performed. Gross observations showed the allograft reaction in control animals to be a well defined phenomenon occurring at 9.0 +/- 0.7 days. In contrast the rejection process in animals that received i.v. ConA was a poorly defined prolonged process occurring at 14.8 +/- 3.9 days (single 75-mg dose of ConA), and 19.0 +/- 2.2 days (75 mg 1 day before and 25 mg 3 days after grafting). In monkeys that received the double dose schedule of ConA, histopathological studies showed distinct retardation of the rejection reaction with reduced lymphocytic infiltration of the graft-host junction. Control grafts showed almost complete rejection in 7-9 days while allografts on ConA-treated animals showed corresponding degrees of destruction only by the 15th day. These studies indicate that ConA does have an immunosuppressive effect in vivo in monkeys. The local and systemic toxic effects of ConA encountered in these animals have been reported and its haematological effects in vivo briefly described.

Focusing on sex-difference in prolongation of allograft survival time, we have performed skin grafts between fully allogeneic rat strains, AO (RT1u) and DA (RT1a) with an immunosuppressant, cyclosporine. Isografted skins survived indefinitely, whereas allografts were severely rejected at days 7-9 without immunosuppressive treatment. When adult male DA rats received CsA (15 mg/kg/day, i.m., for 14 days postoperatively), allogeneic skin was accepted from either male or female AO rats for 38.8 +/- 20.5 days (mean survival time [MST] +/- SD) and for 44.7 +/- 43.3 days (MST +/- SD), respectively, with normal hair growth at around day 17. Additional CsA administration every 5 days after the initial short course treatment was also effective in preventing chronic rejection. Male AO rat skin grafted onto adult male DA rats survived for over 50 days as long as the treatment was carried out. In contrast, when adult female DA rats were used as recipients, only a few days' prolongation was observed in comparison with a non-treated group. The rejection always occurred, even during the initial course of treatment (MST +/- SD): 10.9 +/- 1.6 days). Younger male DA recipients, 5 and 10 weeks old, rejected AO skin within a shorter time, depending on the age. The maximal graft survival was observed when male adult rats more than 14 weeks old were used as recipients. On the other hand, the CsA serum level of female recipients at day 14 was considerably lower than that of males. However, even when the level of females was adjusted to that of males by the administration of a double dosage (30 mg/kg/day), the female recipients consistently rejected the skins (MST +/- SD: 14.5 +/- 1.9 days). Therefore, these results clearly indicate that this male-associated immunosuppressive effect depends upon the sex and age of the recipient animals.

A soluble histocompatibility antigen preparation (HAg) derived by 3M KCl extraction of donor spleen cells has been shown to prolong rat renal allografts in CsA-treated hosts. In the present study, the effect of combined soluble antigen-CsA treatment on cardiac allograft survival was studied in WFu hosts grafted with BUF hearts. Cardiac allograft survival was prolonged in WFu recipients treated with both BUF HAg and CsA compared with survival time in untreated controls or controls treated with HAg or CsA alone. In addition, experiments were performed to test the antigenicity of the HAg extract. BUF extract given sc to WFu hosts before grafting specifically sensitized the hosts to BUF grafts, as shown by the accelerated rejection of BUF grafts but not third-party grafts. Assays to determine the major histocompatibility antigenic determinants present in the extract showed that class I and class II determinants were present.

The immunosuppressive properties of niridazole, an antihelminthic drug, have been investigated in rats. When given orally in a dose of 50 mg/kg, it extended the median survival of cardiac allografts from 7 to 20 days. The immunosuppressive effect was not increased by giving either azathioprine or prednisolone concurrently but when all three drugs were combined, immunosuppression was profound and only two of eight grafts were rejected. Drug combinations incorporating niridazole at a lower dosage or for a shorter period were less effective, and azathioprine and prednisolone on their own or used together prolonged graft survival only marginally in this model. It is concluded that niridazole is a powerful immunosuppressive drug in this species and a synergistic effect can be obtained by using it in combination with azathioprine and prednisolone.

Pretreatment of LEW rats with cyclosporin A (10 mg/kg/day orally for 14 days) plus 10(8) DA or (DA X LEW)F1 spleen lymphocytes on two occasions markedly prolonged the survival of subsequent DA renal allografts. The lymphocytotoxic antibody response was suppressed completely and renal biopsies showed a marked mononuclear cell infiltrate, but no other manifestations of rejection. Neither pretreatment with cyclosporin A alone nor pretreatment with splenic lymphocytes alone had any effect on the subsequent immune reaction. The immunosuppressive effect generated was dependent upon the dose of lymphocytes given, because pretreatment with 10(7) cells on two occasions plus cyclosporin A was relatively ineffective at prolonging renal allograft survival. Pretreatment with 10(8) (DA X LEW)F1 spleen cells plus cyclosporin A was also an effective combination, and ruled out the possibility that graft-versus-host (GVH) disease was responsible for the observed immunosuppression. This pretreatment protocol exhibited specificity in terms of rejection of a third-party (PVG) renal allograft, but not in terms of the lymphocytotoxic antibody response to this graft. Chimerism was not detected in long-term surviving animals using a 51Cr release assay. When pretreatment was performed in LEW rats with a DA skin allograft plus cyclosporin A, a subsequent DA renal allograft was rejected normally, in combination with the skin graft. These findings suggest that clonal deletion had not occurred in these pretreatment protocols, but that a shift in immunoregulatory mechanisms was responsible for the long survival. There are possible clinical implications for the use of pretreatment schedules using donor antigen and cyclosporin A.

SUMMARY Rhesus monkeys given ultracentrifuged normal horse globulin (NHy) i.v. prior to antilymphocyte globulin (ALG) treatment became sensitized rather than tolerant to horse globulin, in the majority of cases. The animals' reactivity to the foreign protein was assessed by measuring antibodies at regular intervals. The possibly enhanced immunosuppressive effect of a standardized ALG course and the severity of localized or generalized complications (presumably attributable to the presence of antibodies) were studied also. A pretreatment course of 4 injections of 10 mg NHγ/kg given on 4 consecutive days during the week prior to ALG treatment led to a degree of tolerance in a few cases; additional immunosuppression with high doses of Imuran did not seem to increase the likelihood of our being able to induce tolerance. The implications of the results, in relation to the current clinical practice of giving NHγ prior to ALG treatment, are discussed.

The effect of pretransplant specific blood transfusions and irradiation of the donor were studied in total orthotopic small bowel transplantation in rats, with the aim of ameliorating the graft-versus-host reaction. Syngeneic transplantation with or without irradiation of the donor with 10 Gy showed that small bowel transplantation is compatible with a normal nutritional status, when no rejection is involved. Transplantation in the histoincompatible WAG-to-BN combination without pretreatment resulted in rejection of the small bowel grafts in 16.6 +/- 2.7 days. Pretreatment with 3 BN blood transfusions to the WAG donor did not prolong the survival time; surprisingly, the transfusions induced a more-severe GVH reaction. Irradiation of the donor with 10 Gy was very effective in ameliorating the GVH disease, but the absence of the immunosuppressive effect of the GVH disease did lead to an accelerated graft rejection (7.5 +/- 0.9 days).

The sera of 12 patients with mechanical trauma were studied to determine C3 levels and activation. The injury severity score (ISS) was then related to serum C3 levels and activation. It was found that in the immediate postinjury period, serum C3 activation occurred in cases where ISS was greater than or equal to 12. The mean ISS of patients with complement activation was 25.2. In comparison, in patients with nonactivation of complement, the mean ISS was 9.5 (p less than 0.05). Serum C3 levels were inversely related to ISS. The mean serum C3 level of patients with ISS greater than or equal to 12 was 73.3 mg% and mean serum C3 level with ISS less than 12 was 109.4 mg%. This difference was again statistically significant (p less than 0.05). There is indication that complement depletion occurs in the immediate postinjury period in moderate to severe injury (ISS greater than or equal to 12). This finding could explain, in part, the immunosuppressive effect of trauma and can be used as a marker to predict possible septic complications.

Total lymphoid irradiation by itself can produce sufficient immunosuppression to prolong the survival of a variety of organ allografts in experimental animals. The degree of prolongation is dose-dependent and is limited by the toxicity that occurs with higher doses. Total lymphoid irradiation is more effective before transplantation than after, but when used after transplantation can be combined with pharmacologic immunosuppression to achieve a positive effect. In some animal models, total lymphoid irradiation induces an environment in which fully allogeneic bone marrow will engraft and induce permanent chimerism in the recipients who are then tolerant to organ allografts from the donor strain. If total lymphoid irradiation is ever to have clinical applicability on a large scale, it would seem that it would have to be under circumstances in which tolerance can be induced. However, in some animal models graft-versus-host disease occurs following bone marrow transplantation, and methods to obviate its occurrence probably will be needed if this approach is to be applied clinically. In recent years, patient and graft survival rates in renal allograft recipients treated with conventional immunosuppression have improved considerably, and thus the impetus to utilize total lymphoid irradiation for its immunosuppressive effect alone is less compelling. For example, in our institution, the current one-year patient and graft survival rates in recipients of kidneys from cadaver donors are 91 and 84 per cent in those treated with cyclosporine and 94 and 80 per cent in those treated with conventional immunosuppression. Similar results might also be achieved by protocols that use total lymphoid irradiation as an immunosuppressant, but it will be difficult to improve over the current results with cyclosporine or conventional immunosuppression, at least for primary transplantation. The future of total lymphoid irradiation probably lies in devising protocols in which maintenance immunosuppression can be eliminated, or nearly eliminated, altogether. Such protocols are effective in rodents. Whether they can be applied to clinical transplantation remains to be seen.

Cell-mediated immune response was measured in 23 patients with ovarian cystadenocarcinoma, 38 patients with benign ovarian tumor, and 44 healthy volunteers. The method used two indexes: the lymphocyte response per unit volume of peripheral blood to phytohemagglutinin (PHA) and the immunosuppressive effect of serum on the response of normal lymphocytes to PHA stimulation. The lymphocyte response per 50 microliter peripheral blood did not differ significantly between patients with ovarian cancer and healthy volunteers. The serum effect, in contrast, differed significantly between malignant and benign ovarian tumors, and was found to increase significantly even when the cancer masses were as small as about 5 x 5 x 5 cm in size, ie, in FIGO Stage I. It is our belief that the measurement of the serum effect in patients with any ovarian tumor enables the early detection of ovarian cancer.